Google Groups no longer supports new Usenet posts or subscriptions. Historical content remains viewable.
Dismiss
FIGHT AGING! NEWSLETTER May 20th 2013
18 views
Skip to first unread message
More Granularity
May 19, 2013, 7:10:58 PM5/19/13
to
FIGHT AGING! NEWSLETTER
May 20th 2013
The Fight Aging! Newsletter is a weekly email containing news,
opinions, and happenings for people interested in aging science and
engineered longevity: making use of diet, lifestyle choices,
technology, and proven medical advances to live healthy, longer lives.
This newsletter is published under the Creative Commons Attribution
3.0 license. In short, this means that you are encouraged to republish
and rewrite it in any way you see fit, the only requirements being
that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe to the Fight Aging! Newsletter, please
visit the newsletter site:
http://www.fightaging.org/newsletter/
CONTENT
-Reviewing the Results of Calorie Restriction Primate Studies
-Are the Most Influential Futurists Those Who Put in the Work to
Make Their Visions Real?
-SENS Research Foundation is the Watering Hole, Not the Herd
-Telomere Length: Cause of Aging or Marker of Aging?
-Be Dubious About Longevity Hotspots
-Discussion
-Latest Headlines from Fight Aging!
-A Possible Biomarker for Senescent Cells
-Inhibiting ICMT as a Progeria Therapy
-Excess Body Fat Hardens Arteries
-Therapeutic Cloning Attained
-The Immune System Ages More Slowly in Women
-Considering Anti-Amyloid Immunotherapy
-Membrane Pacemaker Hypothesis and Ames Dwarf Mice
-On Methionine Restriction
-Amphibian Species with a Chemical Defence Live Longer
-Children of Long-Lived Parents Resistant to Dementia
REVIEWING THE RESULTS OF CALORIE RESTRICTION PRIMATE STUDIES
http://www.fightaging.org/archives/2013/05/reviewing-the-results-of-calorie-restriction-primate-studies.php
In the past few years two ongoing studies of long term calorie
restriction (CR) in primates have started to publish their results on
longevity. Both research programs have been underway for more than 20
years, one run by the National Institute on Aging and the other by the
University of Wisconsin-Madison. Researchers have followed small
groups of rhesus monkeys to see how the benefits to health and life
expectancy resulting from a restricted calorie intake compare with
those obtained in mice and other short-lived species. At this point
the results are ambiguous, unfortunately: one study shows a modest
gain in life expectancy that has been debated, while the other shows
no gain in life expectancy, and that result has also been debated.
Calorie restriction does produce considerable benefits in short term
measures of health in rhesus monkeys and humans, that much is
definitive, but the present consensus in the research community is
that it doesn't greatly extend life in longer-lived primates - perhaps
a few years at most in humans. Differences and issues in the two
primate studies mean that effects of this size on longevity may never
be clear from the data generated. Other factors will wash it out, such
as differences in the diet fed to the control groups, or the different
age at which calorie restriction started. Certainly the results so far
support the conjecture that calorie restriction is exceedingly good
for health but doesn't have the same impressive effects on longevity
as it does in short-lived animals. Why that is the case is a puzzle to
be solved - but not one that has a great deal of relevance to the
future of human longevity. One would hope that we'll be a long way
down the road to rejuvenation therapies by the time another set of
better constructed primate studies are nearing completion.
You'll find a long article over at the SENS Research Foundation that
examines the NIA and Wisconsin primate studies, their differences, and
their results in great detail - but I'm just going to skip ahead and
quote some of the conclusions:
CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics
"In this post, I have sketched out in detail two major possible
interpretations of the disparate mortality outcomes in the NIA and
WNPRC nonhuman primate CR studies. The "Diminishing Returns"
hypothesis posits that the health and longevity benefits of "CR"
reported in the WNPRC study were merely the unsurprising results of
one group of animals being fed a high-sucrose, low-nutrient chow on a
literally ad libitum basis, and another group being kept to portions
of that diet low enough to avoid the deranged metabolisms flowing from
obesity and (possibly) fructose toxicity. In this interpretation, the
more severe restrictions of energy intake imposed at the NIA -
particularly when the chow to which access was restricted may have
been healthier to begin with - led to no further health benefit,
because there are none to be gained: the dramatic age-retarding
effects of CR observed in laboratory rodents and other species do not
translate into longevous species such as primates, and the sole
benefit of controlling energy intake is avoidance of overweight and
obesity.
The "Dose-Response" hypothesis begins from the same interpretation of
the WNPRC study, but posits that far from being excessive (or, at
best, superfluous) to that required for good health, the additional
energy restriction imposed at NIA were too little, and imposed during
too narrow a window, to elicit a clear signal in health and lifespan
benefits; this is supported by the evidence that the NIA primates were
not especially hungry, and only weakly and inconsistently exhibited
improvements in risk factors and endocrine signatures of CR that are
seen both in life-extending CR in rodents, and in humans under
rigorous CR.
Unfortunately, it seems very unlikely that this question will be
resolved. Even the narrow question of whether the age-retarding
effects of CR in laboratory rodents translate into nonhuman primates
could only be established with confidence after yet another trial in
nonhuman primates. [Such] a study is extremely unlikely in light of
the enormous expense of the first two trials, disappointment (and
possibly embarrassment) with the results, [and] the ill winds for
nonhuman primate research. [Even] if such a well-designed and
well-executed study were initiated: what then? Supposing that support
were maintained for the duration of the experiment [it] would be a
further three decades before the earliest point at which survival data
could be reported.
The timescales involved in resolving these questions cannot be
reconciled with the immediate imperatives that drive us to pose them.
With the scale of the humanitarian, economic, and social crisis that
looms in the coming decades due to global demographic aging and
associated ill-health, the near-term need for effective interventions
against the aging process could not be greater. Whether CR can retard
aging in nonhuman primates or not; whether it can retard aging in
humans or not; whether even effective CR mimetics can somehow be
shepherded through clinical trials - even the most optimistic
projection for retarding aging through such approaches is inadequate
to the needs and suffering of aging world."
The point made in the article is the same one that should be made for
all means of slowing the pace of aging by altering metabolism, whether
by the use of drugs to replicate some of the changes caused by calorie
restriction or via other mechanisms. These are very difficult and
challenging projects, certainly very expensive in time and funds, and
which will produce poor and uncertain end results even if successful.
Ways to modestly slow aging do nothing for people who are already old,
and we will grow old waiting for success in the development of drugs
that can safely tinker our metabolisms into a state of slower aging.
The better approach is that outlined by the SENS Research Foundation:
targeted therapies to repair the known forms of cellular and molecular
damage that cause aging. This path is cheaper, more certain, and the
resulting therapies will be capable of rejuvenation - of reversing
degenerative aging, not just slowing it down a little. They will be
greatly beneficial for the old, and extend the length of life lived in
health and vigor. This is why I say that calorie restriction studies
are irrelevant to the future of our health and longevity: the only
thing that really matters is whether or not the SENS vision or similar
repair therapies are prioritized, funded, and developed.
ARE THE MOST INFLUENTIAL FUTURISTS THOSE WHO PUT IN THE WORK TO MAKE
THEIR VISIONS REAL?
http://www.fightaging.org/archives/2013/05/are-the-most-influential-futurists-those-who-put-in-the-work-to-make-their-visions-real.php
We'll take a short excursion into ranking futurists for today,
prompted by a recent article that offers a (transhumanism-slanted)
opinion on the identity of the most important futurists of the past
few decades.
The Most Significant Futurists of the Past 50 Years
"Our visions of the future tend to be forged in the pages of science
fiction. But for the past half-century, a number of prominent
thinkers, activists, and scientists have made significant
contributions to our understanding of what the future could look like.
Here are 10 recent futurists you absolutely need to know about.
Needless to say, there were dozens upon dozens of amazing futurists
who could have been included in this article, so it wasn't easy to
pare down this list. But given the width and breadth of futurist
discourse, we decided to select thinkers whose contributions should be
considered seminal and highly influential to their field of study."
Those selected include Robert Ettinger, one of the founders of modern
cryonics, and Aubrey de Grey, who presently works to make his SENS
roadmap to human rejuvenation a reality. Ray Kurzweil is notably
absent from the list.
It isn't mentioned as a selection criteria in the article, but I think
that ranking the importance of futurists by how effectively they help
to create the future that they envisage isn't all that bad of an idea.
Advocates and popularists play a needed role in moving from vision to
reality, but progress also needs people to perform and orchestrate the
actual work of research and development. Kurzweil, for example, is a
popularist and an advocate with respect to his futurism: beyond the
books and films and persuasion his day job as an inventor and
entrepreneur is so far largely irrelevant to the future he envisages.
I don't think anyone can argue that he isn't important in the arena of
ideas regarding machine intelligence, accelerating change, and how
this will all play out in the decades ahead. But how much more
important would Kurzweil be if, for example, he had decided a decade
or two back to create a company like Zyvex as a long term play to
advance molecular manufacturing, or something equivalent in AI work?
In contrast Ettinger and de Grey both founded successful organizations
devoted to realizing their particular visions: the Cryonics Institute
and the SENS Research Foundation. Both were instrumental in creating
the groundwork and the early community of supporters to enable a new
industry and branch of research in applied medicine. That seems like
the best approach to futurism to me: not just persuasion, but also
working to create the change you want to see in the world.
SENS RESEARCH FOUNDATION IS THE WATERING HOLE, NOT THE HERD
http://www.fightaging.org/archives/2013/05/sens-research-foundation-is-the-watering-hole-not-the-herd.php
If you visit Fight Aging! on a regular basis you'll know that I
strongly favor the SENS Research Foundation and the approach taken by
its founders, advisors, and staff to speed the development of human
rejuvenation. I think we could do with another ten or twenty similar
organizations, and certainly a hundredfold increase in the funding for
rejuvenation research, but right now we have just the one. So send the
Foundation a donation if you're feeling flush today, because there's
no-one else out there at the moment who can do as much for your future
longevity with that money.
Or rather I should say that there are dozens and possibly hundreds of
people out there who can do as much for your future longevity with
those funds - it's just that you don't know who they are. Would you
know enough to chase down William Bains in the UK and ask him to work
on AGE-breaker drugs for glucosepane, for example? Or pick the group
at the Buck Institute best placed work on ways to selectively destroy
senescent cells by interfering in their characteristic biology? Or
have Janko Nikolich-Žugich in Arizona work on restoring the aged
immune system by removing unwanted T cells? Of course not. But there
is a whole world of researchers out there with useful specialist
knowledge and who are these days quite willing to work on the
foundation technologies needed for human rejuvenation - provided that
the funding can be found.
Organizations like the SENS Research Foundation are the interface
between you and the research community: the Foundation staff provide
domain knowledge and relationships needed in order to direct funds
effectively. Without their work it would be impossible for folk like
you or I to help make this field of science move faster - we wouldn't
know where to start or who to talk to, never mind where to send funds,
and finding out would be so costly in comparison to what we could
donate as to make the whole exercise pointless.
The SENS Research Foundation is the watering hole, not the herd. It is
the gateway, not the city. It is the door to a network of researchers
who are interested in human rejuvenation, but that network is a
greater and broader thing than the Foundation. I bring up this point
because many people look no further than the gateway: they see the
SENS Research Foundation and think of an enclosed group, off to one
side of the scientific community, doing its own thing in isolation,
and therefore easy to dismiss. For all that this point of view is
absolutely incorrect, it is not uncommon. You'll see it liberally
applied to biotechnology companies, noted laboratories, and other
organizations that are also gateways to broader scientific networks.
People look at an organization, see its staff performing some research
work in its own domain, but fail to see beyond that to take in the
great tree of relationships and connections behind the name plate.
The greatest achievement of the folk behind the SENS Research
Foundation (and the Methuselah Foundation before it) is their
construction of a lasting and growing network of supporters of
rejuvenation research within the life sciences. This was quite the
task over the past decade and involved a lot of persuasion, changing
the culture of the research community to become more receptive towards
longevity science, building relationships, holding conferences, and
tireless advocacy. It is that web of relationships, and not the
existence of the Foundation per se, that enables growth in funding and
progress towards the goal of ending aging. As for all areas of human
endeavor, it is relationships and networking that make the world turn:
the Foundation is a mailbox, a guidebook, and a banner for a larger
community, an outgrowth of that community even, and it is the
community that gets things done.
This is worth bearing in mind, because it's all to easy to focus on
organizations rather than people and thus miss the whole point of the
exercise.
TELOMERE LENGTH: CAUSE OF AGING OR MARKER OF AGING?
http://www.fightaging.org/archives/2013/05/telomere-length-cause-of-aging-or-marker-of-aging.php
Telomeres are repeating sequences of nucleic acids that cap the ends
of chromosomes in the cell nucleus and stop actual gene-coding DNA
from being chopped off when a cell divides. The mechanisms of DNA
replication require extra leg room at the ends of the strand, a
trailing sequence that is not copied over to the new strand under
assembly - and the primary role of telomeres is to be the part that is
dropped on the floor. A little of their length is thus lost with every
cell division. This shortening acts as a clock to count cell
divisions, and cells with very short telomeres stop replicating - they
either enter cellular senescence (which ideally then causes the immune
system to destroy them) or destroy themselves directly via programmed
cell death mechanisms.
Telomere length is more dynamic than this simple picture, however. In
some cell populations, such as the various types of stem cell that
maintain tissues and produce new cells to replace those lost or
damaged, an enzyme called telomerase continually lengthens telomeres
so as to allow a cell lineage to continue dividing indefinitely.
Ordinary, non-stem cell populations exhibit a range of telomere
lengths, some short, some long. You might imagine that a population of
cells replenished more frequently or recently by stem cells will have
longer telomeres on average. A population that is receiving less
support might have shorter telomeres. Researchers have shown that a
higher proportion of short telomeres in white blood cells correlates
well with ill health or stress, and somewhat correlates with age. Some
more complex measures of telomere length, a step above just taking the
average, have been shown to correlate well with age, however, and
other techniques do a fair job of predicting future life expectancy in
laboratory animals.
A few years back a brace of startup biotech companies were aiming to
address aspects of aging by lengthening telomeres through the use of
telomerase. None of that went anywhere, unfortunately, but it's
possible that they were just too early - it is frequently the case
that all of the first batch of companies in a new area of
biotechnology fail. It's a tough business to be in. I was a skeptic at
the time regarding their potential for success based on my expectation
that telomere length will prove not to be a root cause of aging.
Nonetheless, researchers are demonstrating extension of life in mice
through telomerase these days, but it is as yet unknown as to exactly
why this works. Perhaps it makes stem cells work harder to maintain
tissues, perhaps there is just one critically limiting type of stem
cell or tissue that benefits from more telomerase, or perhaps it
involves other effects causes by increased levels of telomerase that
have nothing to do with telomere length. It is worth bearing in mind
that there are considerable differences in natural levels of
telomerase and the resulting telomere dynamics between mice and
people, however. Telomerase therapy is probably not something you'd
want to just up and try without the research community first obtaining
a much greater understanding of why it works to extend life in mice.
Why? Well, the risk of telomere lengthening in humans is cancer. Any
mechanism that globally, or possibly even narrowly, extends telomere
length in people will raise the risk of suffering cancer. The whole
system of telomere dynamics and cellular senescence is intimately tied
to the processes of cancer suppression, while all cancers evolve ways
of lengthening their telomeres to allow unlimited cell division.
Boosting your telomerase levels looks a lot more risky to me than,
say, undergoing first generation stem cell transplants.
There continues to be a lot of activity in telomere research and
development. The present brace of telomere-related biotech startups
are commercializing ways to measure telomere length rather than extend
it. The products are tests that will at first add another measure to
inform patients on the state of their health, then possibly act as an
effective biomarker of biological age, and perhaps later prove useful
in further research if it turns out that telomerase-based therapies
can be beneficial in humans.
How Long Will You Live?
"A growing number of researchers say telomere length is a critically
important indicator of how old we really are, and of how many healthy
years we may have in front of us. A new industry is sprouting up
around the science of longevity, offering telomere testing to the
public - and Nobel laureate Elizabeth Blackburn is a notable part of
it. Her company, Telome Health, is set to launch a telomere test later
this year, joining a handful of others that already do. Like a
cholesterol or blood-pressure test, telomere testing could one day
become standard in doctors' offices.
And maybe in the future, we'll be able to slow or reverse the effects
of aging -the vision of researchers searching for ways to boost
telomerase, a goal already achieved in lab mice. Some are already
marketing so-called "telomerase activators" to a public hungry for
ways to stop the clock, although no such drugs have been approved.
With so many companies rushing to come on board, "there's a lot of
weird stuff going on out there," cautions Jerry W. Shay of the
University of Texas Southwestern Medical Center, an expert on cell
biology and telomere length."
Certainly you should be looking askance at any group that's selling
herbal "telomerase activators" - it's the standard garbage from the
supplement marketplace, and sadly that's the place that formerly
funded companies doing original research often end up. It's hard to
make money doing something useful in medical research, but
depressingly easy to make money doing something useless in the
supplement business. The traditional model here is to grab a little
research that's somewhat relevant, scare up a bunch of Chinese herb
extracts, and then hope that if you market the thing hard enough it'll
overcome the obvious ineffectiveness and pointlessness. If you can buy
out the shell of a company formerly doing research to try to profit
from its one-time reputation, then all the better. Caveat emptor is
the watchword, as ever.
So where do telomeres fit in the taxonomy of cause versus secondary
effect in aging? Because of the dynamic nature of telomere length I'm
given to think that it's a secondary effect: get sick and average
telomere length in white blood cells shortens; get well and it
lengthens again. This sounds very much like a system responding to
circumstances, and those circumstances most likely include the general
level of cellular damage, inflammation, and metabolic waste products -
all of which grow with age. As for so many other similar questions
about aging, the fastest and cheapest way to answer this question
about telomere length is to implement the Strategies for Engineered
Negligible Senescence (SENS): build the biotechnologies to repair
these forms of damage and then see what happens to telomere length
once its done. That is a good deal easier at this point than obtaining
a full understanding of the aging of human biology.
None of the above precludes short telomeres from causing further
damage or changes of their own, of course. Aging proceeds as a cascade
of harmful effects as damage causes further damage and flailing
biological systems cope badly with the new circumstances they find
themselves in. Here is a recent article on how telomere length can
impact gene expression and thus the operation of metabolism in a
previously unsuspected way, for example:
Telomeres Affect Gene Expression
"DUX4, a gene responsible for the genetic disease facioscapulohumeral
muscular dystrophy (FSHD), is normally silenced because it sits next
to a telomere - a protective DNA sequence that caps the ends of
chromosomes, according to [a recent study]. But as telomeres shorten,
as they do with age, DUX4 expression climbs, which may explain the
late onset of FSHD. Another gene, called FRG2, which sits 100
kilobases away from the telomere, is also affected by telomere length.
"This was completely unexpected. We think that DUX4 and FRG2 are the
tip of an iceberg." Due to shrinking telomeres, many genes might
gradually become more active as we get older, which may be important
for several diseases of old age. "This represents a very significant
general advance in our understanding of how telomere shortening may
affect human biology.""
BE DUBIOUS ABOUT LONGEVITY HOTSPOTS
http://www.fightaging.org/archives/2013/05/be-dubious-about-longevity-hotspots.php
"Cui bono?", "to whose benefit?", is a question that should never be
far from mind. It is rarely the case that the loudest threads in our
grand, connected cultural conversation represent the best, the most
useful, or the most virtuous of what is possible. That is just as true
in any subculture as it is in the mainstream: follow the money and
much becomes clear.
Longevity hotspots might not be a term familiar to you, but Blue Zones
might be thanks to a fair degree of publicity for that latter term.
They mean the same thing, but the latter is a brand rather than a
description. A small industry associated with this brand is devoted to
promoting the idea that some parts of the world exhibit pockets of
exceptional human longevity. It is convenient for various
businesspeople to act as though this is proven beyond a doubt and that
the root causes involve aspects of local culture, diet, and lifestyle
that can be packaged up and sold. So the world goes on: this sort of
thing is a textbook example of how small science projects on minor
aspects of human longevity can spawn commercial monstrosities set on
muddying the waters, promoting myths, and profiting from the
credulous.
It is by no means certain that longevity hotspots exist in actuality,
or at least not in the sense that Blue Zone business ventures would
like you to think, but those most interested in carrying on a dialog
on this topic - i.e. marketing folk involved in tourism, diet,
lifestyle coaching, and so forth - don't really care to hear that
message. Nonetheless:
Designating longevity hotspots: cautions concerning the instability of
per capita centenarian estimates
"Estimates of per capita centenarians in a Utah population varied
between one per 12,864 and one per 4,675, depending on the data that
were used, the population assumptions that were made, and the boundary
limits that were employed. In general, caution is warranted in claims
about the existence of longevity hotspots."
Performing any sort of statistical study on human populations in a
given geographical area, even on something as apparently simple as
age, is enormously complex. People move and data is ever incomplete or
outright false. Some locations attract the wealthy in large numbers, a
demographic already well correlated with greater life expectancy. When
a region in the US with good demographic data can produce a threefold
range of results for a simple population question, one has to wonder
about the accuracy of other studies - and the smaller the group the
less helpful that statistical procedures become.
This is not to say that there is nothing to be learned by comparing
different populations with different lifestyles, but I would be
extremely surprised to see the end results be anything other than
additional support for the value of exercise and calorie restriction
(and derived measures such as body mass index). These line items
strongly correlate with health in large statistical studies.
Neither exercise nor calorie restriction will let you reliably live to
see 100, however. The only thing that can achieve that goal is
significant progress in new medical science. Longevity hotspots are,
like so much of what is discussed in relation to aging these days,
nothing but a sideshow - something that occupies time and energy and
attention, and all to no good end. That the data is most likely flawed
and what little science there was is now largely buried beneath an
industry that strives to make money by promoting magical thinking and
ignorance just makes the joke a little more black.
DISCUSSION
The highlights and headlines from the past week follow below. Remember
- if you like this newsletter, the chances are that your friends will
find it useful too. Forward it on, or post a copy to your favorite
online communities. Encourage the people you know to pitch in and make
a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
A POSSIBLE BIOMARKER FOR SENESCENT CELLS
Friday, May 17, 2013
http://www.fightaging.org/archives/2013/05/a-possible-biomarker-for-senescent-cells.php
There are any number of techniques under development that allow
individual cells to be destroyed provided that you can distinguish
them from their neighbors: the challenge is in finding characteristic
differences in the cells you want destroyed, such as cancer cells or
senescent cells. Most of the efforts aimed at producing targeted cell
destruction therapies are taking place in the cancer research
community, but senescent cells accumulate with age and contribute to
degenerative aging - they must also be destroyed. Unfortunately good
ways to target senescent cells are somewhat lacking. Candidate
mechanisms are emerging, however, and here is another of them:
"Due to its role in aging and antitumor defense, cellular senescence
has recently attracted increasing interest. However, [the] detection
of senescent cells remains difficult due to the lack of specific
biomarkers. ndeed, most determinants of cellular senescence, such as
the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated
cytokines, are not exclusively observed in senescence, but can also
occur in other types of stress responses. In addition, alterations
like SAHF or DNA-SCARS formation are frequently observed, but not
necessarily a mandatory feature or exclusive to senescent cells.
The current gold standard for the detection of senescence is the
so-called senescence-associated β-galactosidase (SA-β-Gal) activity.
Although SA-β-Gal has been first suggested as a distinct enzyme, its
activity is derived from lysosomal β-Gal encoded by the GLB1 gene.
β-Gal is an accepted marker of senescence, but its reliability and
specificity have been questioned, as a positive β-Gal reaction has
also been detected in human cancer cells that were chemically induced
to differentiate, or upon contact inhibition. Moreover, several cell
types, such as epithelial cells and murine fibroblasts generally show
a weak β-Gal staining.
In the present study, we investigated several lysosomal hydrolases for
their suitability as senescence markers and identified α-fucosidase,
a lysosomal glycosidase involved in the breakdown of glycoproteins,
oligosaccharides and glycolipids, as a novel biomarker for senescence.
We demonstrate that α-fucosidase is upregulated [in] all canonical
types of cellular senescence, including replicative, DNA damage- and
oncogene-induced senescence. Our results suggest that detection of
α-fucosidase might be a highly valuable biomarker for senescence in
general and in particular in those cases where SA-β-Gal activity
fails to properly discriminate between senescent- and non-senescent
cells."
INHIBITING ICMT AS A PROGERIA THERAPY
Friday, May 17, 2013
http://www.fightaging.org/archives/2013/05/inhibiting-icmt-as-a-progeria-therapy.php
Progress towards a therapy for the rare accelerated aging condition
progeria continues. It remains unclear as to whether the mechanisms
responsible for progeria exist in normal aging to a level that is in
any way significant. Progeria is caused by malformed prelamin A, and
tiny amounts of broken prelamin A can be found in old tissues - but it
would really require a therapy for progeria that addressed the issues
with prelamin A to easily find out whether this has any meaningful
contribution to normal aging.
"The classical form of progeria, called Hutchinson-Gilford Progeria
Syndrome (HGPS), is caused by a spontaneous mutation, which means that
it is not inherited from the parents. Children with HGPS usually die
in their teenage years from myocardial infarction and stroke.
The progeria mutation occurs in the protein prelamin A and causes it
to accumulate in an inappropriate form in the membrane surrounding the
nucleus. The target enzyme, called ICMT, attaches a small chemical
group to one end of prelamin A. Blocking ICMT, therefore, prevents the
attachment of the chemical group to prelamin A and significantly
reduced the ability of the mutant protein to induce progeria. "We are
collaborating with a group in Singapore that has developed candidate
ICMT inhibitor drugs and we will now test them on mice with progeria.
Because the drugs have not yet been tested in humans, it will be a few
years before we know whether these drugs will be appropriate for the
treatment of progeria."
"The resemblance between progeria patients and normally-aged
individuals is striking and it is tempting to speculate that progeria
is a window into our normal aging process. The children develop
osteoporosis, myocardial infarction, stroke, and muscle weakness. They
display poor growth and lose their hair, but interestingly, they do
not develop dementia or cancer." [The researchers are] also studying
the impact of inhibiting ICMT on the normal aging process in mice."
EXCESS BODY FAT HARDENS ARTERIES
Thursday, May 16, 2013
http://www.fightaging.org/archives/2013/05/excess-body-fat-hardens-arteries.php
There are all sorts of good reasons to avoid becoming fat. Excess fat
tissue is linked to an increased risk of all the common diseases of
aging, and correlates well with a shorter life expectancy and higher
lifetime medical expenditures. Fat tissue creates higher levels of
chronic inflammation and alters the signaling environment in the body,
causing a wide range of changes. Here is another of them:
"Having too much body fat makes arteries become stiff after middle
age, a new study has revealed. In young people, blood vessels appear
to be able to compensate for the effects of obesity. But after middle
age, this adaptability is lost, and arteries become progressively
stiffer as body fat rises - potentially increasing the risk of dying
from cardiovascular disease. The researchers suggest that the harmful
effects of body fat may be related to the total number of years that a
person is overweight in adulthood. Further research is needed to find
out when the effects of obesity lead to irreversible damage to the
heart and arteries, they said.
Researchers [scanned] 200 volunteers to measure the speed of blood
flow in the aorta, the biggest artery in the body. Blood travels more
quickly in stiff vessels than in healthy elastic vessels, so this
allowed them to work out how stiff the walls of the aorta were using
an MRI scanner. In young adults, those with more body fat had less
stiff arteries. However, after the age of 50 increasing body fat was
associated with stiffer arteries in both men and women. Body fat
percentage, which can be estimated by passing a small electric current
through the body, was more closely linked with artery stiffness than
body mass index, which is based just on weight and height.
"We don't know for sure how body fat makes arteries stiffer, but we do
know that certain metabolic products in the blood may progressively
damage the elastic fibres in our blood vessels. Understanding these
processes might help us to prevent the harmful effects of obesity.""
THERAPEUTIC CLONING ATTAINED
Thursday, May 16, 2013
http://www.fightaging.org/archives/2013/05/therapeutic-cloning-attained.php
Therapeutic cloning or somatic cell nuclear transfer are names given
to a method of producing embryonic stem cells from a patient's own
cells. These embryonic stem cells could then be used to generate cells
of any type as a basis for regenerative therapies. Making the process
work has proven to be challenging, however, both from a technical
point of view and thanks to misguided attempts to make it illegal. In
recent years the focus shifted towards work on induced pluripotent
stem cells instead, but a research group now claims success in the
original goal:
"Scientists [have] successfully reprogrammed human skin cells to
become embryonic stem cells capable of transforming into any other
cell type in the body. It is believed that stem cell therapies hold
the promise of replacing cells damaged through injury or illness. The
technique used [is] a variation of a commonly used method called
somatic cell nuclear transfer, or SCNT. It involves transplanting the
nucleus of one cell, containing an individual's DNA, into an egg cell
that has had its genetic material removed. The unfertilized egg cell
then develops and eventually produces stem cells.
Previous unsuccessful attempts by several labs showed that human egg
cells appear to be more fragile than eggs from other species.
Therefore, known reprogramming methods stalled before stem cells were
produced. To solve this problem, the [researchers] studied various
alternative approaches first developed in monkey cells and then
applied to human cells. Through moving findings between monkey cells
and human cells, the researchers were able to develop a successful
method. The key to this success was finding a way to prompt egg cells
to stay in a state called "metaphase" during the nuclear transfer
process. Metaphase is a stage in the cell's natural division process
(meiosis) when genetic material aligns in the middle of the cell
before the cell divides. The research team found that chemically
maintaining metaphase throughout the transfer process prevented the
process from stalling and allowed the cells to develop and produce
stem cells."
THE IMMUNE SYSTEM AGES MORE SLOWLY IN WOMEN
Wednesday, May 15, 2013
http://www.fightaging.org/archives/2013/05/the-immune-system-ages-more-slowly-in-women.php
Women tend to live longer than men, and there are any number of
competing explanations as to why this is the case. They range from
risk of mortality relating to lifestyle choices to evolutionary
selection operating on the male role in reproduction to various
differences in biochemistry that exist between the genders. That the
female immune system ages more slowly shouldn't be terribly surprising
- but it might be cause or consequence.
"Women's immune systems age more slowly than men's, [and] the slower
decline in a woman's immune system may contribute to women living
longer than men. Researchers looked at the blood of healthy volunteers
in Japan, ranging in age between 20 and 90 years old; in both sexes
the total number of white blood cells per person decreased with age.
The number of neutrophils decreased for both sexes and lymphocytes
decreased in men and increased in women. Younger men generally have
higher levels of lymphocytes than similarly aged women, so as aging
happens, the number of lymphocytes becomes comparable.
Looking in more detail it became apparent that the rate in decline in
T cells and B cells was slower for women than men. Both CD4+ T cells
and NK cells increased with age, and the rate of increase was higher
in women than men. Similarly an age-related decline in IL-6 and IL-10
was worse in men. There was also a age-dependent decrease in red blood
cells for men but not women.
"The process of aging is different for men and women for many reasons.
Women have more oestrogen than men which seems to protect them from
cardiovascular disease until menopause. Sex hormones also affect the
immune system, especially certain types of lymphocytes. Because people
age at different rates a person's immunological parameters could be
used to provide an indication of their true biological age.""
CONSIDERING ANTI-AMYLOID IMMUNOTHERAPY
Wednesday, May 15, 2013
http://www.fightaging.org/archives/2013/05/considering-anti-amyloid-immunotherapy.php
Amyloids are solid masses that form in tissues as a result of
misfolded proteins. The amount of amyloid increases with age, perhaps
due to a failure of mechanisms that keep the levels of damaged or
misfolded proteins under control, and this is thought to cause harm
and contribute to degenerative aging. In most cases researchers are
still lacking a full understanding of the mechanisms involved,
however. At the very least having solid clumps and fibrils present
where they shouldn't exist can disrupt tissue integrity or even cause
larger scale issues such as clogging blood vessels.
One approach to removing amyloid involves the use of the immune
system. Immune therapies direct immune cells to attack and break down
a specific target, and much of the innovation in their use as a
therapy to remove amyloid is happening in the Alzheimer's research
community. That condition is associated with amyloid beta, but we can
hope that any successful therapies will prove adaptable to other forms
of amyloid and thus applicable to human rejuvenation.
"Alzheimer's disease (AD) is the most common dementia in the
industrialized world, with prevalence rates well over 30% in the over
80-years-old population. AD is strongly associated with Amyloid-beta
(Abeta) protein aggregation, which results in extracellular plaques in
the brain, and according to the amyloid cascade hypothesis appeared to
be a promising target for the development of AD therapeutics.
Within the past decade convincing data has arisen positioning the
soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD.
However, different Abeta aggregate species are described but their
remarkable metastability hampers the identification of a target
species for immunization. Passive immunotherapy with monoclonal
antibodies (mAbs) against Abeta is in late clinical development but
recently the two most advanced mAbs, Bapineuzumab and Solanezumab,
targeting an N-terminal or central epitope, respectively, failed to
meet their target of improving or stabilizing cognition and function.
Preliminary data from off-label treatment of a small cohort for 3
years with intravenous polyclonal immunoglobulins (IVIG) that appear
to target different conformational epitopes indicate a cognitive
stabilization. Thus, it might be the more promising strategy reducing
the whole spectrum of Abeta-aggregates than to focus on a single
aggregate species for immunization."
MEMBRANE PACEMAKER HYPOTHESIS AND AMES DWARF MICE
Tuesday, May 14, 2013
http://www.fightaging.org/archives/2013/05/membrane-pacemaker-hypothesis-and-ames-dwarf-mice.php
Ames dwarf mice lack growth hormone and as a consequence live much
longer than their peers. Here the biochemistry of this lineage is
considered in light of the membrane pacemaker hypothesis of aging,
which suggests that the degree of resistance to oxidative damage in
cell membranes is a driving factor in determining longevity. Thus
similar species with different proportions of more resistant and less
resistant molecules making up their cell membranes have different life
spans. Is it possible that this can happen within a species thanks to
genetic engineering of the sort that produced the Ames dwarf mouse
lineage?
"Membrane fatty acid (FA) composition is correlated with longevity in
mammals. The "membrane pacemaker hypothesis of ageing" proposes that
animals which cellular membranes contain high amounts of
polyunsaturated FAs (PUFAs) have shorter life spans because their
membranes are more susceptible to peroxidation and further oxidative
damage. It remains to be shown, however, that long-lived phenotypes
such as the Ames dwarf mouse have membranes containing fewer PUFAs and
thus being less prone to peroxidation, as would be predicted from the
membrane pacemaker hypothesis of ageing.
Here, we show that across four different tissues, i.e., muscle, heart,
liver and brain as well as in liver mitochondria, Ames dwarf mice
possess membrane phospholipids containing between 30 and 60 % PUFAs
(depending on the tissue), which is similar to PUFA contents of their
normal-sized, short-lived siblings. However, we found that that Ames
dwarf mice membrane phospholipids were significantly poorer in n-3
PUFAs. While lack of a difference in PUFA contents is contradicting
the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the
long-lived mice provides some support for the membrane pacemaker
hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed
most for causing oxidative damage. By comparing tissue composition
between 1-, 2- and 6-month-old mice in both phenotypes, we found that
membranes differed both in quantity of PUFAs and in the prevalence of
certain PUFAs. In sum, membrane composition in the Ames dwarf mouse
supports the concept that tissue FA composition is related to
longevity."
At some point a research group will find a way to alter only membrane
constituent molecules and no other factors in laboratory mice, which
should go some way towards quantifying the effect on aging and
longevity. The challenge with using any of the well known long-lived
lineages of mice is that many aspects of their metabolism are
different - it is difficult to point to any one of those and talk
about how important it may or may not be to extended longevity given
the presence of the others.
ON METHIONINE RESTRICTION
Tuesday, May 14, 2013
http://www.fightaging.org/archives/2013/05/on-methionine-restriction-1.php
Levels of the essential amino acid methionine in the diet appear to be
involved in generating the beneficial effects of calorie restriction
on health and longevity. Some portion of the resulting changes in the
operation of metabolism is based on sensing low levels of methionine.
It is thus possible that humans might obtain benefits comparable to
those generated by calorie restriction from a sensibly constructed
low-methionine diet with a normal calorie intake. The research in
support of this supposition is still sparse in comparison to that for
calorie restriction, however.
"It was first reported in 1993 that rats subjected to a diet
restricted in methionine (MR) enjoyed comparable life spans to rats
that were on caloric restriction (CR). In the first experiments,
methionine was reduced to ⅕ its normal level in the diet, and growth
of the rats was severely stunted. We can't live entirely without
methionine - the body would not be able to make any proteins at all.
Restricting methionine is likely to have impacts on growth, health,
and wellbeing that are as yet unstudied in humans. Rats fed a diet
without methionine developed steatohepatitis (fatty liver), anemia and
lost two thirds of their body weight over 5 weeks. In one experiment
where methionine was severely restricted but not eliminated entirely,
⅕ of the mice died, and the other ⅘ went on to live longer than
control mice.
Here's a clue about why methionine is special. The instructions for
making proteins is coded into DNA, via the genetic code, which
specifies words of 3 DNA letters, each corresponding to one of the 20
amino acids. The genetic code also contains "punctuation",
instructions to start and stop. The "start codon" is also the word
for methionine. Every chain of amino acids that the body constructs
begins with methionine. No methionine - no protein synthesis. A
shortage of methionine means that the body is inhibited in making
every kind of protein. More genes are expressed (more proteins
synthesized) as the body grows older. Perhaps methionine restriction
is putting a brake on this production of extra proteins that are not
produced when we're young, and that contribute to aging.
Methionine restriction in practice involves eating foods that are low
in methionine. Though all protein has methionine, some protein
sources are much lower in methionine than others. All animal sources
(including milk and especially eggs) are high in methionine. So a
methionine-restricted diet is a vegan diet, not just any vegan diet,
but a subset of vegan protein sources. There appear to be no general
rules. For example, almonds are a good source of low-methionine
protein, but Brazil nuts are terrible. Even a strict vegan diet would
only reduce methionine intake by about 1/2. Extrapolating from the
rodent experiments, we may need to reduce by ~ 3/4 before crossing a
threshold where benefits kick in."
AMPHIBIAN SPECIES WITH A CHEMICAL DEFENCE LIVE LONGER
Monday, May 13, 2013
http://www.fightaging.org/archives/2013/05/amphibian-species-with-a-chemical-defence-live-longer.php
When it comes to evolutionary influences on longevity, the evidence
supports the idea that species with a high mortality rate due to
external causes (e.g. being eaten) will tend to be short-lived. There
is no evolutionary pressure to develop the biological mechanisms that
will lead to longer reproductive lives if near all individuals are
killed comparatively early in life. This study is a novel way to add
further supporting evidence to this point of view:
"Evolutionary hypotheses for ageing generally predict that delayed
senescence should evolve in organisms that experience lower extrinsic
mortality. Thus, one might expect species that are highly toxic or
venomous (i.e. chemically protected) will have longer lifespans than
related species that are not likewise protected. This remarkable
relationship has been suggested to occur in amphibians and snakes.
First, we show that chemical protection is highly conserved in several
lineages of amphibians and snakes. Therefore, accounting for
phylogenetic autocorrelation is critical when conservatively testing
evolutionary hypotheses because species may possess similar
longevities and defensive attributes simply through shared ancestry.
Herein, we compare maximum longevity of chemically protected and
nonprotected species, controlling for potential nonindependence of
traits among species using recently available phylogenies.
Our analyses confirm that longevity is positively correlated with body
size in both groups which is consistent with life-history theory. We
also show that maximum lifespan was positively associated with
chemical protection in amphibian species but not in snakes. Chemical
protection is defensive in amphibians, but primarily offensive
(involved in prey capture) in snakes. Thus, we find that although
chemical defence in amphibians favours long life, there is no evidence
that chemical offence in snakes does the same."
CHILDREN OF LONG-LIVED PARENTS RESISTANT TO DEMENTIA
Monday, May 13, 2013
http://www.fightaging.org/archives/2013/05/children-of-long-lived-parents-resistant-to-dementia.php
Some degree of human longevity is genetic rather than the result of
environment and lifestyle choice; researchers have guessed that
perhaps 25% of variations are genetic, but this is hardly a firm
number. It appears to be the case that survival at extreme old age is
more influenced by genetic variations than it is in early old age, for
example. Given that some predisposition to longevity is thus
inherited, it isn't surprising to find that risk levels for specific
conditions of aging also correlate with familial longevity:
"Based on comparisons of people in their 90s, their spouses, siblings,
children and their children's spouses, researchers found that the
offspring of people with exceptional longevity were about 40 percent
less likely than peers to be cognitively impaired between ages 65 and
79. "It's not necessarily that these individuals never become
cognitively impaired, but what it seems like is that there is a
delayed onset of cognitive impairment."
For the new study, the researchers used data on cognitive impairment
from 1,870 people who are part of the Long Life Family Study, which
includes volunteer participants in New York, Massachusetts,
Pennsylvania and Denmark. The study included 1,510 people with a
family history of longevity and 360 of their spouses, but for this
study, researchers used information on just the volunteers who were 89
years old or older when they were recruited.
Overall, the researchers found that about 6 percent of the volunteers'
children were cognitively impaired between ages 65 and 79 years old,
compared to 13 percent of their spouses and about 11 percent of their
cousins. Among the study's long-lived older generation, participants
were just as likely to be cognitively impaired by about age 90 as
their siblings or spouses. "These families seem relatively protected,
but once they reach extreme old age - say after 90 (years old) - their
rates of cognitive impairment become comparable.""
May 20th 2013
The Fight Aging! Newsletter is a weekly email containing news,
opinions, and happenings for people interested in aging science and
engineered longevity: making use of diet, lifestyle choices,
technology, and proven medical advances to live healthy, longer lives.
This newsletter is published under the Creative Commons Attribution
3.0 license. In short, this means that you are encouraged to republish
and rewrite it in any way you see fit, the only requirements being
that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe to the Fight Aging! Newsletter, please
visit the newsletter site:
http://www.fightaging.org/newsletter/
CONTENT
-Reviewing the Results of Calorie Restriction Primate Studies
-Are the Most Influential Futurists Those Who Put in the Work to
Make Their Visions Real?
-SENS Research Foundation is the Watering Hole, Not the Herd
-Telomere Length: Cause of Aging or Marker of Aging?
-Be Dubious About Longevity Hotspots
-Discussion
-Latest Headlines from Fight Aging!
-A Possible Biomarker for Senescent Cells
-Inhibiting ICMT as a Progeria Therapy
-Excess Body Fat Hardens Arteries
-Therapeutic Cloning Attained
-The Immune System Ages More Slowly in Women
-Considering Anti-Amyloid Immunotherapy
-Membrane Pacemaker Hypothesis and Ames Dwarf Mice
-On Methionine Restriction
-Amphibian Species with a Chemical Defence Live Longer
-Children of Long-Lived Parents Resistant to Dementia
REVIEWING THE RESULTS OF CALORIE RESTRICTION PRIMATE STUDIES
http://www.fightaging.org/archives/2013/05/reviewing-the-results-of-calorie-restriction-primate-studies.php
In the past few years two ongoing studies of long term calorie
restriction (CR) in primates have started to publish their results on
longevity. Both research programs have been underway for more than 20
years, one run by the National Institute on Aging and the other by the
University of Wisconsin-Madison. Researchers have followed small
groups of rhesus monkeys to see how the benefits to health and life
expectancy resulting from a restricted calorie intake compare with
those obtained in mice and other short-lived species. At this point
the results are ambiguous, unfortunately: one study shows a modest
gain in life expectancy that has been debated, while the other shows
no gain in life expectancy, and that result has also been debated.
Calorie restriction does produce considerable benefits in short term
measures of health in rhesus monkeys and humans, that much is
definitive, but the present consensus in the research community is
that it doesn't greatly extend life in longer-lived primates - perhaps
a few years at most in humans. Differences and issues in the two
primate studies mean that effects of this size on longevity may never
be clear from the data generated. Other factors will wash it out, such
as differences in the diet fed to the control groups, or the different
age at which calorie restriction started. Certainly the results so far
support the conjecture that calorie restriction is exceedingly good
for health but doesn't have the same impressive effects on longevity
as it does in short-lived animals. Why that is the case is a puzzle to
be solved - but not one that has a great deal of relevance to the
future of human longevity. One would hope that we'll be a long way
down the road to rejuvenation therapies by the time another set of
better constructed primate studies are nearing completion.
You'll find a long article over at the SENS Research Foundation that
examines the NIA and Wisconsin primate studies, their differences, and
their results in great detail - but I'm just going to skip ahead and
quote some of the conclusions:
CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics
"In this post, I have sketched out in detail two major possible
interpretations of the disparate mortality outcomes in the NIA and
WNPRC nonhuman primate CR studies. The "Diminishing Returns"
hypothesis posits that the health and longevity benefits of "CR"
reported in the WNPRC study were merely the unsurprising results of
one group of animals being fed a high-sucrose, low-nutrient chow on a
literally ad libitum basis, and another group being kept to portions
of that diet low enough to avoid the deranged metabolisms flowing from
obesity and (possibly) fructose toxicity. In this interpretation, the
more severe restrictions of energy intake imposed at the NIA -
particularly when the chow to which access was restricted may have
been healthier to begin with - led to no further health benefit,
because there are none to be gained: the dramatic age-retarding
effects of CR observed in laboratory rodents and other species do not
translate into longevous species such as primates, and the sole
benefit of controlling energy intake is avoidance of overweight and
obesity.
The "Dose-Response" hypothesis begins from the same interpretation of
the WNPRC study, but posits that far from being excessive (or, at
best, superfluous) to that required for good health, the additional
energy restriction imposed at NIA were too little, and imposed during
too narrow a window, to elicit a clear signal in health and lifespan
benefits; this is supported by the evidence that the NIA primates were
not especially hungry, and only weakly and inconsistently exhibited
improvements in risk factors and endocrine signatures of CR that are
seen both in life-extending CR in rodents, and in humans under
rigorous CR.
Unfortunately, it seems very unlikely that this question will be
resolved. Even the narrow question of whether the age-retarding
effects of CR in laboratory rodents translate into nonhuman primates
could only be established with confidence after yet another trial in
nonhuman primates. [Such] a study is extremely unlikely in light of
the enormous expense of the first two trials, disappointment (and
possibly embarrassment) with the results, [and] the ill winds for
nonhuman primate research. [Even] if such a well-designed and
well-executed study were initiated: what then? Supposing that support
were maintained for the duration of the experiment [it] would be a
further three decades before the earliest point at which survival data
could be reported.
The timescales involved in resolving these questions cannot be
reconciled with the immediate imperatives that drive us to pose them.
With the scale of the humanitarian, economic, and social crisis that
looms in the coming decades due to global demographic aging and
associated ill-health, the near-term need for effective interventions
against the aging process could not be greater. Whether CR can retard
aging in nonhuman primates or not; whether it can retard aging in
humans or not; whether even effective CR mimetics can somehow be
shepherded through clinical trials - even the most optimistic
projection for retarding aging through such approaches is inadequate
to the needs and suffering of aging world."
The point made in the article is the same one that should be made for
all means of slowing the pace of aging by altering metabolism, whether
by the use of drugs to replicate some of the changes caused by calorie
restriction or via other mechanisms. These are very difficult and
challenging projects, certainly very expensive in time and funds, and
which will produce poor and uncertain end results even if successful.
Ways to modestly slow aging do nothing for people who are already old,
and we will grow old waiting for success in the development of drugs
that can safely tinker our metabolisms into a state of slower aging.
The better approach is that outlined by the SENS Research Foundation:
targeted therapies to repair the known forms of cellular and molecular
damage that cause aging. This path is cheaper, more certain, and the
resulting therapies will be capable of rejuvenation - of reversing
degenerative aging, not just slowing it down a little. They will be
greatly beneficial for the old, and extend the length of life lived in
health and vigor. This is why I say that calorie restriction studies
are irrelevant to the future of our health and longevity: the only
thing that really matters is whether or not the SENS vision or similar
repair therapies are prioritized, funded, and developed.
ARE THE MOST INFLUENTIAL FUTURISTS THOSE WHO PUT IN THE WORK TO MAKE
THEIR VISIONS REAL?
http://www.fightaging.org/archives/2013/05/are-the-most-influential-futurists-those-who-put-in-the-work-to-make-their-visions-real.php
We'll take a short excursion into ranking futurists for today,
prompted by a recent article that offers a (transhumanism-slanted)
opinion on the identity of the most important futurists of the past
few decades.
The Most Significant Futurists of the Past 50 Years
"Our visions of the future tend to be forged in the pages of science
fiction. But for the past half-century, a number of prominent
thinkers, activists, and scientists have made significant
contributions to our understanding of what the future could look like.
Here are 10 recent futurists you absolutely need to know about.
Needless to say, there were dozens upon dozens of amazing futurists
who could have been included in this article, so it wasn't easy to
pare down this list. But given the width and breadth of futurist
discourse, we decided to select thinkers whose contributions should be
considered seminal and highly influential to their field of study."
Those selected include Robert Ettinger, one of the founders of modern
cryonics, and Aubrey de Grey, who presently works to make his SENS
roadmap to human rejuvenation a reality. Ray Kurzweil is notably
absent from the list.
It isn't mentioned as a selection criteria in the article, but I think
that ranking the importance of futurists by how effectively they help
to create the future that they envisage isn't all that bad of an idea.
Advocates and popularists play a needed role in moving from vision to
reality, but progress also needs people to perform and orchestrate the
actual work of research and development. Kurzweil, for example, is a
popularist and an advocate with respect to his futurism: beyond the
books and films and persuasion his day job as an inventor and
entrepreneur is so far largely irrelevant to the future he envisages.
I don't think anyone can argue that he isn't important in the arena of
ideas regarding machine intelligence, accelerating change, and how
this will all play out in the decades ahead. But how much more
important would Kurzweil be if, for example, he had decided a decade
or two back to create a company like Zyvex as a long term play to
advance molecular manufacturing, or something equivalent in AI work?
In contrast Ettinger and de Grey both founded successful organizations
devoted to realizing their particular visions: the Cryonics Institute
and the SENS Research Foundation. Both were instrumental in creating
the groundwork and the early community of supporters to enable a new
industry and branch of research in applied medicine. That seems like
the best approach to futurism to me: not just persuasion, but also
working to create the change you want to see in the world.
SENS RESEARCH FOUNDATION IS THE WATERING HOLE, NOT THE HERD
http://www.fightaging.org/archives/2013/05/sens-research-foundation-is-the-watering-hole-not-the-herd.php
If you visit Fight Aging! on a regular basis you'll know that I
strongly favor the SENS Research Foundation and the approach taken by
its founders, advisors, and staff to speed the development of human
rejuvenation. I think we could do with another ten or twenty similar
organizations, and certainly a hundredfold increase in the funding for
rejuvenation research, but right now we have just the one. So send the
Foundation a donation if you're feeling flush today, because there's
no-one else out there at the moment who can do as much for your future
longevity with that money.
Or rather I should say that there are dozens and possibly hundreds of
people out there who can do as much for your future longevity with
those funds - it's just that you don't know who they are. Would you
know enough to chase down William Bains in the UK and ask him to work
on AGE-breaker drugs for glucosepane, for example? Or pick the group
at the Buck Institute best placed work on ways to selectively destroy
senescent cells by interfering in their characteristic biology? Or
have Janko Nikolich-Žugich in Arizona work on restoring the aged
immune system by removing unwanted T cells? Of course not. But there
is a whole world of researchers out there with useful specialist
knowledge and who are these days quite willing to work on the
foundation technologies needed for human rejuvenation - provided that
the funding can be found.
Organizations like the SENS Research Foundation are the interface
between you and the research community: the Foundation staff provide
domain knowledge and relationships needed in order to direct funds
effectively. Without their work it would be impossible for folk like
you or I to help make this field of science move faster - we wouldn't
know where to start or who to talk to, never mind where to send funds,
and finding out would be so costly in comparison to what we could
donate as to make the whole exercise pointless.
The SENS Research Foundation is the watering hole, not the herd. It is
the gateway, not the city. It is the door to a network of researchers
who are interested in human rejuvenation, but that network is a
greater and broader thing than the Foundation. I bring up this point
because many people look no further than the gateway: they see the
SENS Research Foundation and think of an enclosed group, off to one
side of the scientific community, doing its own thing in isolation,
and therefore easy to dismiss. For all that this point of view is
absolutely incorrect, it is not uncommon. You'll see it liberally
applied to biotechnology companies, noted laboratories, and other
organizations that are also gateways to broader scientific networks.
People look at an organization, see its staff performing some research
work in its own domain, but fail to see beyond that to take in the
great tree of relationships and connections behind the name plate.
The greatest achievement of the folk behind the SENS Research
Foundation (and the Methuselah Foundation before it) is their
construction of a lasting and growing network of supporters of
rejuvenation research within the life sciences. This was quite the
task over the past decade and involved a lot of persuasion, changing
the culture of the research community to become more receptive towards
longevity science, building relationships, holding conferences, and
tireless advocacy. It is that web of relationships, and not the
existence of the Foundation per se, that enables growth in funding and
progress towards the goal of ending aging. As for all areas of human
endeavor, it is relationships and networking that make the world turn:
the Foundation is a mailbox, a guidebook, and a banner for a larger
community, an outgrowth of that community even, and it is the
community that gets things done.
This is worth bearing in mind, because it's all to easy to focus on
organizations rather than people and thus miss the whole point of the
exercise.
TELOMERE LENGTH: CAUSE OF AGING OR MARKER OF AGING?
http://www.fightaging.org/archives/2013/05/telomere-length-cause-of-aging-or-marker-of-aging.php
Telomeres are repeating sequences of nucleic acids that cap the ends
of chromosomes in the cell nucleus and stop actual gene-coding DNA
from being chopped off when a cell divides. The mechanisms of DNA
replication require extra leg room at the ends of the strand, a
trailing sequence that is not copied over to the new strand under
assembly - and the primary role of telomeres is to be the part that is
dropped on the floor. A little of their length is thus lost with every
cell division. This shortening acts as a clock to count cell
divisions, and cells with very short telomeres stop replicating - they
either enter cellular senescence (which ideally then causes the immune
system to destroy them) or destroy themselves directly via programmed
cell death mechanisms.
Telomere length is more dynamic than this simple picture, however. In
some cell populations, such as the various types of stem cell that
maintain tissues and produce new cells to replace those lost or
damaged, an enzyme called telomerase continually lengthens telomeres
so as to allow a cell lineage to continue dividing indefinitely.
Ordinary, non-stem cell populations exhibit a range of telomere
lengths, some short, some long. You might imagine that a population of
cells replenished more frequently or recently by stem cells will have
longer telomeres on average. A population that is receiving less
support might have shorter telomeres. Researchers have shown that a
higher proportion of short telomeres in white blood cells correlates
well with ill health or stress, and somewhat correlates with age. Some
more complex measures of telomere length, a step above just taking the
average, have been shown to correlate well with age, however, and
other techniques do a fair job of predicting future life expectancy in
laboratory animals.
A few years back a brace of startup biotech companies were aiming to
address aspects of aging by lengthening telomeres through the use of
telomerase. None of that went anywhere, unfortunately, but it's
possible that they were just too early - it is frequently the case
that all of the first batch of companies in a new area of
biotechnology fail. It's a tough business to be in. I was a skeptic at
the time regarding their potential for success based on my expectation
that telomere length will prove not to be a root cause of aging.
Nonetheless, researchers are demonstrating extension of life in mice
through telomerase these days, but it is as yet unknown as to exactly
why this works. Perhaps it makes stem cells work harder to maintain
tissues, perhaps there is just one critically limiting type of stem
cell or tissue that benefits from more telomerase, or perhaps it
involves other effects causes by increased levels of telomerase that
have nothing to do with telomere length. It is worth bearing in mind
that there are considerable differences in natural levels of
telomerase and the resulting telomere dynamics between mice and
people, however. Telomerase therapy is probably not something you'd
want to just up and try without the research community first obtaining
a much greater understanding of why it works to extend life in mice.
Why? Well, the risk of telomere lengthening in humans is cancer. Any
mechanism that globally, or possibly even narrowly, extends telomere
length in people will raise the risk of suffering cancer. The whole
system of telomere dynamics and cellular senescence is intimately tied
to the processes of cancer suppression, while all cancers evolve ways
of lengthening their telomeres to allow unlimited cell division.
Boosting your telomerase levels looks a lot more risky to me than,
say, undergoing first generation stem cell transplants.
There continues to be a lot of activity in telomere research and
development. The present brace of telomere-related biotech startups
are commercializing ways to measure telomere length rather than extend
it. The products are tests that will at first add another measure to
inform patients on the state of their health, then possibly act as an
effective biomarker of biological age, and perhaps later prove useful
in further research if it turns out that telomerase-based therapies
can be beneficial in humans.
How Long Will You Live?
"A growing number of researchers say telomere length is a critically
important indicator of how old we really are, and of how many healthy
years we may have in front of us. A new industry is sprouting up
around the science of longevity, offering telomere testing to the
public - and Nobel laureate Elizabeth Blackburn is a notable part of
it. Her company, Telome Health, is set to launch a telomere test later
this year, joining a handful of others that already do. Like a
cholesterol or blood-pressure test, telomere testing could one day
become standard in doctors' offices.
And maybe in the future, we'll be able to slow or reverse the effects
of aging -the vision of researchers searching for ways to boost
telomerase, a goal already achieved in lab mice. Some are already
marketing so-called "telomerase activators" to a public hungry for
ways to stop the clock, although no such drugs have been approved.
With so many companies rushing to come on board, "there's a lot of
weird stuff going on out there," cautions Jerry W. Shay of the
University of Texas Southwestern Medical Center, an expert on cell
biology and telomere length."
Certainly you should be looking askance at any group that's selling
herbal "telomerase activators" - it's the standard garbage from the
supplement marketplace, and sadly that's the place that formerly
funded companies doing original research often end up. It's hard to
make money doing something useful in medical research, but
depressingly easy to make money doing something useless in the
supplement business. The traditional model here is to grab a little
research that's somewhat relevant, scare up a bunch of Chinese herb
extracts, and then hope that if you market the thing hard enough it'll
overcome the obvious ineffectiveness and pointlessness. If you can buy
out the shell of a company formerly doing research to try to profit
from its one-time reputation, then all the better. Caveat emptor is
the watchword, as ever.
So where do telomeres fit in the taxonomy of cause versus secondary
effect in aging? Because of the dynamic nature of telomere length I'm
given to think that it's a secondary effect: get sick and average
telomere length in white blood cells shortens; get well and it
lengthens again. This sounds very much like a system responding to
circumstances, and those circumstances most likely include the general
level of cellular damage, inflammation, and metabolic waste products -
all of which grow with age. As for so many other similar questions
about aging, the fastest and cheapest way to answer this question
about telomere length is to implement the Strategies for Engineered
Negligible Senescence (SENS): build the biotechnologies to repair
these forms of damage and then see what happens to telomere length
once its done. That is a good deal easier at this point than obtaining
a full understanding of the aging of human biology.
None of the above precludes short telomeres from causing further
damage or changes of their own, of course. Aging proceeds as a cascade
of harmful effects as damage causes further damage and flailing
biological systems cope badly with the new circumstances they find
themselves in. Here is a recent article on how telomere length can
impact gene expression and thus the operation of metabolism in a
previously unsuspected way, for example:
Telomeres Affect Gene Expression
"DUX4, a gene responsible for the genetic disease facioscapulohumeral
muscular dystrophy (FSHD), is normally silenced because it sits next
to a telomere - a protective DNA sequence that caps the ends of
chromosomes, according to [a recent study]. But as telomeres shorten,
as they do with age, DUX4 expression climbs, which may explain the
late onset of FSHD. Another gene, called FRG2, which sits 100
kilobases away from the telomere, is also affected by telomere length.
"This was completely unexpected. We think that DUX4 and FRG2 are the
tip of an iceberg." Due to shrinking telomeres, many genes might
gradually become more active as we get older, which may be important
for several diseases of old age. "This represents a very significant
general advance in our understanding of how telomere shortening may
affect human biology.""
BE DUBIOUS ABOUT LONGEVITY HOTSPOTS
http://www.fightaging.org/archives/2013/05/be-dubious-about-longevity-hotspots.php
"Cui bono?", "to whose benefit?", is a question that should never be
far from mind. It is rarely the case that the loudest threads in our
grand, connected cultural conversation represent the best, the most
useful, or the most virtuous of what is possible. That is just as true
in any subculture as it is in the mainstream: follow the money and
much becomes clear.
Longevity hotspots might not be a term familiar to you, but Blue Zones
might be thanks to a fair degree of publicity for that latter term.
They mean the same thing, but the latter is a brand rather than a
description. A small industry associated with this brand is devoted to
promoting the idea that some parts of the world exhibit pockets of
exceptional human longevity. It is convenient for various
businesspeople to act as though this is proven beyond a doubt and that
the root causes involve aspects of local culture, diet, and lifestyle
that can be packaged up and sold. So the world goes on: this sort of
thing is a textbook example of how small science projects on minor
aspects of human longevity can spawn commercial monstrosities set on
muddying the waters, promoting myths, and profiting from the
credulous.
It is by no means certain that longevity hotspots exist in actuality,
or at least not in the sense that Blue Zone business ventures would
like you to think, but those most interested in carrying on a dialog
on this topic - i.e. marketing folk involved in tourism, diet,
lifestyle coaching, and so forth - don't really care to hear that
message. Nonetheless:
Designating longevity hotspots: cautions concerning the instability of
per capita centenarian estimates
"Estimates of per capita centenarians in a Utah population varied
between one per 12,864 and one per 4,675, depending on the data that
were used, the population assumptions that were made, and the boundary
limits that were employed. In general, caution is warranted in claims
about the existence of longevity hotspots."
Performing any sort of statistical study on human populations in a
given geographical area, even on something as apparently simple as
age, is enormously complex. People move and data is ever incomplete or
outright false. Some locations attract the wealthy in large numbers, a
demographic already well correlated with greater life expectancy. When
a region in the US with good demographic data can produce a threefold
range of results for a simple population question, one has to wonder
about the accuracy of other studies - and the smaller the group the
less helpful that statistical procedures become.
This is not to say that there is nothing to be learned by comparing
different populations with different lifestyles, but I would be
extremely surprised to see the end results be anything other than
additional support for the value of exercise and calorie restriction
(and derived measures such as body mass index). These line items
strongly correlate with health in large statistical studies.
Neither exercise nor calorie restriction will let you reliably live to
see 100, however. The only thing that can achieve that goal is
significant progress in new medical science. Longevity hotspots are,
like so much of what is discussed in relation to aging these days,
nothing but a sideshow - something that occupies time and energy and
attention, and all to no good end. That the data is most likely flawed
and what little science there was is now largely buried beneath an
industry that strives to make money by promoting magical thinking and
ignorance just makes the joke a little more black.
DISCUSSION
The highlights and headlines from the past week follow below. Remember
- if you like this newsletter, the chances are that your friends will
find it useful too. Forward it on, or post a copy to your favorite
online communities. Encourage the people you know to pitch in and make
a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
A POSSIBLE BIOMARKER FOR SENESCENT CELLS
Friday, May 17, 2013
http://www.fightaging.org/archives/2013/05/a-possible-biomarker-for-senescent-cells.php
There are any number of techniques under development that allow
individual cells to be destroyed provided that you can distinguish
them from their neighbors: the challenge is in finding characteristic
differences in the cells you want destroyed, such as cancer cells or
senescent cells. Most of the efforts aimed at producing targeted cell
destruction therapies are taking place in the cancer research
community, but senescent cells accumulate with age and contribute to
degenerative aging - they must also be destroyed. Unfortunately good
ways to target senescent cells are somewhat lacking. Candidate
mechanisms are emerging, however, and here is another of them:
"Due to its role in aging and antitumor defense, cellular senescence
has recently attracted increasing interest. However, [the] detection
of senescent cells remains difficult due to the lack of specific
biomarkers. ndeed, most determinants of cellular senescence, such as
the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated
cytokines, are not exclusively observed in senescence, but can also
occur in other types of stress responses. In addition, alterations
like SAHF or DNA-SCARS formation are frequently observed, but not
necessarily a mandatory feature or exclusive to senescent cells.
The current gold standard for the detection of senescence is the
so-called senescence-associated β-galactosidase (SA-β-Gal) activity.
Although SA-β-Gal has been first suggested as a distinct enzyme, its
activity is derived from lysosomal β-Gal encoded by the GLB1 gene.
β-Gal is an accepted marker of senescence, but its reliability and
specificity have been questioned, as a positive β-Gal reaction has
also been detected in human cancer cells that were chemically induced
to differentiate, or upon contact inhibition. Moreover, several cell
types, such as epithelial cells and murine fibroblasts generally show
a weak β-Gal staining.
In the present study, we investigated several lysosomal hydrolases for
their suitability as senescence markers and identified α-fucosidase,
a lysosomal glycosidase involved in the breakdown of glycoproteins,
oligosaccharides and glycolipids, as a novel biomarker for senescence.
We demonstrate that α-fucosidase is upregulated [in] all canonical
types of cellular senescence, including replicative, DNA damage- and
oncogene-induced senescence. Our results suggest that detection of
α-fucosidase might be a highly valuable biomarker for senescence in
general and in particular in those cases where SA-β-Gal activity
fails to properly discriminate between senescent- and non-senescent
cells."
INHIBITING ICMT AS A PROGERIA THERAPY
Friday, May 17, 2013
http://www.fightaging.org/archives/2013/05/inhibiting-icmt-as-a-progeria-therapy.php
Progress towards a therapy for the rare accelerated aging condition
progeria continues. It remains unclear as to whether the mechanisms
responsible for progeria exist in normal aging to a level that is in
any way significant. Progeria is caused by malformed prelamin A, and
tiny amounts of broken prelamin A can be found in old tissues - but it
would really require a therapy for progeria that addressed the issues
with prelamin A to easily find out whether this has any meaningful
contribution to normal aging.
"The classical form of progeria, called Hutchinson-Gilford Progeria
Syndrome (HGPS), is caused by a spontaneous mutation, which means that
it is not inherited from the parents. Children with HGPS usually die
in their teenage years from myocardial infarction and stroke.
The progeria mutation occurs in the protein prelamin A and causes it
to accumulate in an inappropriate form in the membrane surrounding the
nucleus. The target enzyme, called ICMT, attaches a small chemical
group to one end of prelamin A. Blocking ICMT, therefore, prevents the
attachment of the chemical group to prelamin A and significantly
reduced the ability of the mutant protein to induce progeria. "We are
collaborating with a group in Singapore that has developed candidate
ICMT inhibitor drugs and we will now test them on mice with progeria.
Because the drugs have not yet been tested in humans, it will be a few
years before we know whether these drugs will be appropriate for the
treatment of progeria."
"The resemblance between progeria patients and normally-aged
individuals is striking and it is tempting to speculate that progeria
is a window into our normal aging process. The children develop
osteoporosis, myocardial infarction, stroke, and muscle weakness. They
display poor growth and lose their hair, but interestingly, they do
not develop dementia or cancer." [The researchers are] also studying
the impact of inhibiting ICMT on the normal aging process in mice."
EXCESS BODY FAT HARDENS ARTERIES
Thursday, May 16, 2013
http://www.fightaging.org/archives/2013/05/excess-body-fat-hardens-arteries.php
There are all sorts of good reasons to avoid becoming fat. Excess fat
tissue is linked to an increased risk of all the common diseases of
aging, and correlates well with a shorter life expectancy and higher
lifetime medical expenditures. Fat tissue creates higher levels of
chronic inflammation and alters the signaling environment in the body,
causing a wide range of changes. Here is another of them:
"Having too much body fat makes arteries become stiff after middle
age, a new study has revealed. In young people, blood vessels appear
to be able to compensate for the effects of obesity. But after middle
age, this adaptability is lost, and arteries become progressively
stiffer as body fat rises - potentially increasing the risk of dying
from cardiovascular disease. The researchers suggest that the harmful
effects of body fat may be related to the total number of years that a
person is overweight in adulthood. Further research is needed to find
out when the effects of obesity lead to irreversible damage to the
heart and arteries, they said.
Researchers [scanned] 200 volunteers to measure the speed of blood
flow in the aorta, the biggest artery in the body. Blood travels more
quickly in stiff vessels than in healthy elastic vessels, so this
allowed them to work out how stiff the walls of the aorta were using
an MRI scanner. In young adults, those with more body fat had less
stiff arteries. However, after the age of 50 increasing body fat was
associated with stiffer arteries in both men and women. Body fat
percentage, which can be estimated by passing a small electric current
through the body, was more closely linked with artery stiffness than
body mass index, which is based just on weight and height.
"We don't know for sure how body fat makes arteries stiffer, but we do
know that certain metabolic products in the blood may progressively
damage the elastic fibres in our blood vessels. Understanding these
processes might help us to prevent the harmful effects of obesity.""
THERAPEUTIC CLONING ATTAINED
Thursday, May 16, 2013
http://www.fightaging.org/archives/2013/05/therapeutic-cloning-attained.php
Therapeutic cloning or somatic cell nuclear transfer are names given
to a method of producing embryonic stem cells from a patient's own
cells. These embryonic stem cells could then be used to generate cells
of any type as a basis for regenerative therapies. Making the process
work has proven to be challenging, however, both from a technical
point of view and thanks to misguided attempts to make it illegal. In
recent years the focus shifted towards work on induced pluripotent
stem cells instead, but a research group now claims success in the
original goal:
"Scientists [have] successfully reprogrammed human skin cells to
become embryonic stem cells capable of transforming into any other
cell type in the body. It is believed that stem cell therapies hold
the promise of replacing cells damaged through injury or illness. The
technique used [is] a variation of a commonly used method called
somatic cell nuclear transfer, or SCNT. It involves transplanting the
nucleus of one cell, containing an individual's DNA, into an egg cell
that has had its genetic material removed. The unfertilized egg cell
then develops and eventually produces stem cells.
Previous unsuccessful attempts by several labs showed that human egg
cells appear to be more fragile than eggs from other species.
Therefore, known reprogramming methods stalled before stem cells were
produced. To solve this problem, the [researchers] studied various
alternative approaches first developed in monkey cells and then
applied to human cells. Through moving findings between monkey cells
and human cells, the researchers were able to develop a successful
method. The key to this success was finding a way to prompt egg cells
to stay in a state called "metaphase" during the nuclear transfer
process. Metaphase is a stage in the cell's natural division process
(meiosis) when genetic material aligns in the middle of the cell
before the cell divides. The research team found that chemically
maintaining metaphase throughout the transfer process prevented the
process from stalling and allowed the cells to develop and produce
stem cells."
THE IMMUNE SYSTEM AGES MORE SLOWLY IN WOMEN
Wednesday, May 15, 2013
http://www.fightaging.org/archives/2013/05/the-immune-system-ages-more-slowly-in-women.php
Women tend to live longer than men, and there are any number of
competing explanations as to why this is the case. They range from
risk of mortality relating to lifestyle choices to evolutionary
selection operating on the male role in reproduction to various
differences in biochemistry that exist between the genders. That the
female immune system ages more slowly shouldn't be terribly surprising
- but it might be cause or consequence.
"Women's immune systems age more slowly than men's, [and] the slower
decline in a woman's immune system may contribute to women living
longer than men. Researchers looked at the blood of healthy volunteers
in Japan, ranging in age between 20 and 90 years old; in both sexes
the total number of white blood cells per person decreased with age.
The number of neutrophils decreased for both sexes and lymphocytes
decreased in men and increased in women. Younger men generally have
higher levels of lymphocytes than similarly aged women, so as aging
happens, the number of lymphocytes becomes comparable.
Looking in more detail it became apparent that the rate in decline in
T cells and B cells was slower for women than men. Both CD4+ T cells
and NK cells increased with age, and the rate of increase was higher
in women than men. Similarly an age-related decline in IL-6 and IL-10
was worse in men. There was also a age-dependent decrease in red blood
cells for men but not women.
"The process of aging is different for men and women for many reasons.
Women have more oestrogen than men which seems to protect them from
cardiovascular disease until menopause. Sex hormones also affect the
immune system, especially certain types of lymphocytes. Because people
age at different rates a person's immunological parameters could be
used to provide an indication of their true biological age.""
CONSIDERING ANTI-AMYLOID IMMUNOTHERAPY
Wednesday, May 15, 2013
http://www.fightaging.org/archives/2013/05/considering-anti-amyloid-immunotherapy.php
Amyloids are solid masses that form in tissues as a result of
misfolded proteins. The amount of amyloid increases with age, perhaps
due to a failure of mechanisms that keep the levels of damaged or
misfolded proteins under control, and this is thought to cause harm
and contribute to degenerative aging. In most cases researchers are
still lacking a full understanding of the mechanisms involved,
however. At the very least having solid clumps and fibrils present
where they shouldn't exist can disrupt tissue integrity or even cause
larger scale issues such as clogging blood vessels.
One approach to removing amyloid involves the use of the immune
system. Immune therapies direct immune cells to attack and break down
a specific target, and much of the innovation in their use as a
therapy to remove amyloid is happening in the Alzheimer's research
community. That condition is associated with amyloid beta, but we can
hope that any successful therapies will prove adaptable to other forms
of amyloid and thus applicable to human rejuvenation.
"Alzheimer's disease (AD) is the most common dementia in the
industrialized world, with prevalence rates well over 30% in the over
80-years-old population. AD is strongly associated with Amyloid-beta
(Abeta) protein aggregation, which results in extracellular plaques in
the brain, and according to the amyloid cascade hypothesis appeared to
be a promising target for the development of AD therapeutics.
Within the past decade convincing data has arisen positioning the
soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD.
However, different Abeta aggregate species are described but their
remarkable metastability hampers the identification of a target
species for immunization. Passive immunotherapy with monoclonal
antibodies (mAbs) against Abeta is in late clinical development but
recently the two most advanced mAbs, Bapineuzumab and Solanezumab,
targeting an N-terminal or central epitope, respectively, failed to
meet their target of improving or stabilizing cognition and function.
Preliminary data from off-label treatment of a small cohort for 3
years with intravenous polyclonal immunoglobulins (IVIG) that appear
to target different conformational epitopes indicate a cognitive
stabilization. Thus, it might be the more promising strategy reducing
the whole spectrum of Abeta-aggregates than to focus on a single
aggregate species for immunization."
MEMBRANE PACEMAKER HYPOTHESIS AND AMES DWARF MICE
Tuesday, May 14, 2013
http://www.fightaging.org/archives/2013/05/membrane-pacemaker-hypothesis-and-ames-dwarf-mice.php
Ames dwarf mice lack growth hormone and as a consequence live much
longer than their peers. Here the biochemistry of this lineage is
considered in light of the membrane pacemaker hypothesis of aging,
which suggests that the degree of resistance to oxidative damage in
cell membranes is a driving factor in determining longevity. Thus
similar species with different proportions of more resistant and less
resistant molecules making up their cell membranes have different life
spans. Is it possible that this can happen within a species thanks to
genetic engineering of the sort that produced the Ames dwarf mouse
lineage?
"Membrane fatty acid (FA) composition is correlated with longevity in
mammals. The "membrane pacemaker hypothesis of ageing" proposes that
animals which cellular membranes contain high amounts of
polyunsaturated FAs (PUFAs) have shorter life spans because their
membranes are more susceptible to peroxidation and further oxidative
damage. It remains to be shown, however, that long-lived phenotypes
such as the Ames dwarf mouse have membranes containing fewer PUFAs and
thus being less prone to peroxidation, as would be predicted from the
membrane pacemaker hypothesis of ageing.
Here, we show that across four different tissues, i.e., muscle, heart,
liver and brain as well as in liver mitochondria, Ames dwarf mice
possess membrane phospholipids containing between 30 and 60 % PUFAs
(depending on the tissue), which is similar to PUFA contents of their
normal-sized, short-lived siblings. However, we found that that Ames
dwarf mice membrane phospholipids were significantly poorer in n-3
PUFAs. While lack of a difference in PUFA contents is contradicting
the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the
long-lived mice provides some support for the membrane pacemaker
hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed
most for causing oxidative damage. By comparing tissue composition
between 1-, 2- and 6-month-old mice in both phenotypes, we found that
membranes differed both in quantity of PUFAs and in the prevalence of
certain PUFAs. In sum, membrane composition in the Ames dwarf mouse
supports the concept that tissue FA composition is related to
longevity."
At some point a research group will find a way to alter only membrane
constituent molecules and no other factors in laboratory mice, which
should go some way towards quantifying the effect on aging and
longevity. The challenge with using any of the well known long-lived
lineages of mice is that many aspects of their metabolism are
different - it is difficult to point to any one of those and talk
about how important it may or may not be to extended longevity given
the presence of the others.
ON METHIONINE RESTRICTION
Tuesday, May 14, 2013
http://www.fightaging.org/archives/2013/05/on-methionine-restriction-1.php
Levels of the essential amino acid methionine in the diet appear to be
involved in generating the beneficial effects of calorie restriction
on health and longevity. Some portion of the resulting changes in the
operation of metabolism is based on sensing low levels of methionine.
It is thus possible that humans might obtain benefits comparable to
those generated by calorie restriction from a sensibly constructed
low-methionine diet with a normal calorie intake. The research in
support of this supposition is still sparse in comparison to that for
calorie restriction, however.
"It was first reported in 1993 that rats subjected to a diet
restricted in methionine (MR) enjoyed comparable life spans to rats
that were on caloric restriction (CR). In the first experiments,
methionine was reduced to ⅕ its normal level in the diet, and growth
of the rats was severely stunted. We can't live entirely without
methionine - the body would not be able to make any proteins at all.
Restricting methionine is likely to have impacts on growth, health,
and wellbeing that are as yet unstudied in humans. Rats fed a diet
without methionine developed steatohepatitis (fatty liver), anemia and
lost two thirds of their body weight over 5 weeks. In one experiment
where methionine was severely restricted but not eliminated entirely,
⅕ of the mice died, and the other ⅘ went on to live longer than
control mice.
Here's a clue about why methionine is special. The instructions for
making proteins is coded into DNA, via the genetic code, which
specifies words of 3 DNA letters, each corresponding to one of the 20
amino acids. The genetic code also contains "punctuation",
instructions to start and stop. The "start codon" is also the word
for methionine. Every chain of amino acids that the body constructs
begins with methionine. No methionine - no protein synthesis. A
shortage of methionine means that the body is inhibited in making
every kind of protein. More genes are expressed (more proteins
synthesized) as the body grows older. Perhaps methionine restriction
is putting a brake on this production of extra proteins that are not
produced when we're young, and that contribute to aging.
Methionine restriction in practice involves eating foods that are low
in methionine. Though all protein has methionine, some protein
sources are much lower in methionine than others. All animal sources
(including milk and especially eggs) are high in methionine. So a
methionine-restricted diet is a vegan diet, not just any vegan diet,
but a subset of vegan protein sources. There appear to be no general
rules. For example, almonds are a good source of low-methionine
protein, but Brazil nuts are terrible. Even a strict vegan diet would
only reduce methionine intake by about 1/2. Extrapolating from the
rodent experiments, we may need to reduce by ~ 3/4 before crossing a
threshold where benefits kick in."
AMPHIBIAN SPECIES WITH A CHEMICAL DEFENCE LIVE LONGER
Monday, May 13, 2013
http://www.fightaging.org/archives/2013/05/amphibian-species-with-a-chemical-defence-live-longer.php
When it comes to evolutionary influences on longevity, the evidence
supports the idea that species with a high mortality rate due to
external causes (e.g. being eaten) will tend to be short-lived. There
is no evolutionary pressure to develop the biological mechanisms that
will lead to longer reproductive lives if near all individuals are
killed comparatively early in life. This study is a novel way to add
further supporting evidence to this point of view:
"Evolutionary hypotheses for ageing generally predict that delayed
senescence should evolve in organisms that experience lower extrinsic
mortality. Thus, one might expect species that are highly toxic or
venomous (i.e. chemically protected) will have longer lifespans than
related species that are not likewise protected. This remarkable
relationship has been suggested to occur in amphibians and snakes.
First, we show that chemical protection is highly conserved in several
lineages of amphibians and snakes. Therefore, accounting for
phylogenetic autocorrelation is critical when conservatively testing
evolutionary hypotheses because species may possess similar
longevities and defensive attributes simply through shared ancestry.
Herein, we compare maximum longevity of chemically protected and
nonprotected species, controlling for potential nonindependence of
traits among species using recently available phylogenies.
Our analyses confirm that longevity is positively correlated with body
size in both groups which is consistent with life-history theory. We
also show that maximum lifespan was positively associated with
chemical protection in amphibian species but not in snakes. Chemical
protection is defensive in amphibians, but primarily offensive
(involved in prey capture) in snakes. Thus, we find that although
chemical defence in amphibians favours long life, there is no evidence
that chemical offence in snakes does the same."
CHILDREN OF LONG-LIVED PARENTS RESISTANT TO DEMENTIA
Monday, May 13, 2013
http://www.fightaging.org/archives/2013/05/children-of-long-lived-parents-resistant-to-dementia.php
Some degree of human longevity is genetic rather than the result of
environment and lifestyle choice; researchers have guessed that
perhaps 25% of variations are genetic, but this is hardly a firm
number. It appears to be the case that survival at extreme old age is
more influenced by genetic variations than it is in early old age, for
example. Given that some predisposition to longevity is thus
inherited, it isn't surprising to find that risk levels for specific
conditions of aging also correlate with familial longevity:
"Based on comparisons of people in their 90s, their spouses, siblings,
children and their children's spouses, researchers found that the
offspring of people with exceptional longevity were about 40 percent
less likely than peers to be cognitively impaired between ages 65 and
79. "It's not necessarily that these individuals never become
cognitively impaired, but what it seems like is that there is a
delayed onset of cognitive impairment."
For the new study, the researchers used data on cognitive impairment
from 1,870 people who are part of the Long Life Family Study, which
includes volunteer participants in New York, Massachusetts,
Pennsylvania and Denmark. The study included 1,510 people with a
family history of longevity and 360 of their spouses, but for this
study, researchers used information on just the volunteers who were 89
years old or older when they were recruited.
Overall, the researchers found that about 6 percent of the volunteers'
children were cognitively impaired between ages 65 and 79 years old,
compared to 13 percent of their spouses and about 11 percent of their
cousins. Among the study's long-lived older generation, participants
were just as likely to be cognitively impaired by about age 90 as
their siblings or spouses. "These families seem relatively protected,
but once they reach extreme old age - say after 90 (years old) - their
rates of cognitive impairment become comparable.""
Taka
May 21, 2013, 3:53:22 AM5/21/13
to
On May 20, 8:10 am, More Granularity <moregranular...@gmail.com>
wrote:
You see? Fish oil eaters are doomed to fail .... Taka
------------------------
Age (Dordr). 2013 May 3. [Epub ahead of print]
Phospholipid composition and longevity: lessons from Ames dwarf mice.
Valencak TG, Ruf T.
Department of Integrative Biology and Evolution, Research Institute of
Wildlife Ecology, University of Veterinary Medicine, Savoyenstrasse 1,
1160, Vienna, Austria,
Membrane fatty acid (FA) composition is correlated with longevity in
mammals. The "membrane pacemaker hypothesis of ageing" proposes that
animals which cellular membranes contain high amounts of
polyunsaturated FAs (PUFAs) have shorter life spans because their
membranes are more susceptible to peroxidation and further oxidative
damage. It remains to be shown, however, that long-lived phenotypes
such as the Ames dwarf mouse have membranes containing fewer PUFAs and
thus being less prone to peroxidation, as would be predicted from the
membrane pacemaker hypothesis of ageing. Here, we show that across
four different tissues, i.e., muscle, heart, liver and brain as well
as in liver mitochondria, Ames dwarf mice possess membrane
phospholipids containing between 30 and 60 % PUFAs (depending on the
tissue), which is similar to PUFA contents of their normal-sized,
short-lived siblings. However, we found that that Ames dwarf mice
membrane phospholipids were significantly poorer in n-3 PUFAs. While
lack of a difference in PUFA contents is contradicting the membrane
pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived
mice provides some support for the membrane pacemaker hypothesis of
ageing, as n-3 PUFAs comprise those FAs being blamed most for causing
oxidative damage. By comparing tissue composition between 1-, 2- and 6-
month-old mice in both phenotypes, we found that membranes differed
both in quantity of PUFAs and in the prevalence of certain PUFAs. In
sum, membrane composition in the Ames dwarf mouse supports the concept
that tissue FA composition is related to longevity.
PMID: 23640425
wrote:
> FIGHT AGING! NEWSLETTER
> May 20th 2013
> May 20th 2013
> MEMBRANE PACEMAKER HYPOTHESIS AND AMES DWARF MICE
> Tuesday, May 14, 2013http://www.fightaging.org/archives/2013/05/membrane-pacemaker-hypothe...
------------------------
Age (Dordr). 2013 May 3. [Epub ahead of print]
Phospholipid composition and longevity: lessons from Ames dwarf mice.
Valencak TG, Ruf T.
Department of Integrative Biology and Evolution, Research Institute of
Wildlife Ecology, University of Veterinary Medicine, Savoyenstrasse 1,
1160, Vienna, Austria,
Membrane fatty acid (FA) composition is correlated with longevity in
mammals. The "membrane pacemaker hypothesis of ageing" proposes that
animals which cellular membranes contain high amounts of
polyunsaturated FAs (PUFAs) have shorter life spans because their
membranes are more susceptible to peroxidation and further oxidative
damage. It remains to be shown, however, that long-lived phenotypes
such as the Ames dwarf mouse have membranes containing fewer PUFAs and
thus being less prone to peroxidation, as would be predicted from the
membrane pacemaker hypothesis of ageing. Here, we show that across
four different tissues, i.e., muscle, heart, liver and brain as well
as in liver mitochondria, Ames dwarf mice possess membrane
phospholipids containing between 30 and 60 % PUFAs (depending on the
tissue), which is similar to PUFA contents of their normal-sized,
short-lived siblings. However, we found that that Ames dwarf mice
membrane phospholipids were significantly poorer in n-3 PUFAs. While
lack of a difference in PUFA contents is contradicting the membrane
pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived
mice provides some support for the membrane pacemaker hypothesis of
ageing, as n-3 PUFAs comprise those FAs being blamed most for causing
oxidative damage. By comparing tissue composition between 1-, 2- and 6-
month-old mice in both phenotypes, we found that membranes differed
both in quantity of PUFAs and in the prevalence of certain PUFAs. In
sum, membrane composition in the Ames dwarf mouse supports the concept
that tissue FA composition is related to longevity.
vittyguy
May 21, 2013, 10:57:44 AM5/21/13
to
"You see? Fish oil eaters are doomed to fail .... Taka"
Nonsense. The various areas of japan with the longest average life span
consume fatty fish as a usual part of the diet.
Taka
May 21, 2013, 11:41:09 AM5/21/13
to
with the Omega-3 to suppress inflammation, of course. Look at the age
spots on old Japanese, it's all lipofuscin from the "battle" of fish
and vegetable oils ....
Taka
vittyguy
May 21, 2013, 11:50:07 AM5/21/13
to
> "You see? =A0Fish oil eaters are doomed to fail .... =A0 =A0Taka"
>
> Nonsense. =A0The various areas of japan with the longest average life
spa=
life span with much fatty fish suggests.
>
> Nonsense. =A0The various areas of japan with the longest average life
spa=
n
> consume fatty fish as a usual part of the diet.
"If you consume Omega-6, as most Japanese do, you need to balance it with
the Omega-3 to suppress inflammation, of course. Look at the age spots on
old Japanese, it's all lipofuscin from the "battle" of fish and vegetable
oils ...."
Irrelevant nonsense. Consult the subject line again and what the japanese
> consume fatty fish as a usual part of the diet.
"If you consume Omega-6, as most Japanese do, you need to balance it with
the Omega-3 to suppress inflammation, of course. Look at the age spots on
old Japanese, it's all lipofuscin from the "battle" of fish and vegetable
oils ...."
life span with much fatty fish suggests.
John H. Gohde
May 21, 2013, 2:05:49 PM5/21/13
to
Can Taka cool it with his profoundly racist and culturally insensitive
posting?
Taka
May 21, 2013, 10:02:36 PM5/21/13
to
On May 22, 12:50 am, vitty guy wrote:
> Irrelevant nonsense. Consult the subject line again and what the japanese
> life span with much fatty fish suggests.
Japanese longevity is a pension scam. Taka
> Irrelevant nonsense. Consult the subject line again and what the japanese
> life span with much fatty fish suggests.
John H. Gohde
May 22, 2013, 12:42:14 AM5/22/13
to
might want to know.
I bet that that the low-dose radiation that Taka has been swimming in
of late has NOT raised his I.Q. any. Perhaps, it is time for Taka to
retire, since he seems overly concerned about the fate of his P-
Brain. Yep, Taka has clearly been losing it, or should I say inches?
Hmn, can Taka measure it in inches? Maybe Taka should use the cm
scale for his obviously micro P-Brain?
Stunted his entire life, the poor P-Brain. :)
Moi on the other hand has NEVER had to worry about that Department.
Could be why the ladies are always giving moi that stupid look.
LOL Stunted Taka has my condolences.
vittyguy
May 22, 2013, 10:35:10 AM5/22/13
to
> Irrelevant nonsense. =A0Consult the subject line again and what the
japan=
finding oneself, no?
After posting the original I recalled they use much seaweed also in their
diet, another source of omega 3 fatty acids.
japan=
ese
> life span with much fatty fish suggests.
"Japanese longevity is a pension scam. Taka"
Yes, this another ad hoc just so story to fit the corner into which now
> life span with much fatty fish suggests.
"Japanese longevity is a pension scam. Taka"
finding oneself, no?
After posting the original I recalled they use much seaweed also in their
diet, another source of omega 3 fatty acids.
John H. Gohde
May 22, 2013, 5:28:21 PM5/22/13
to
0 new messages