The following is an extract from an article, The Genetics of Ageing, which was written by Cynthia Kenyon and originally appeared in Nature in March 2010.

“For many years, molecular biologists interested in regulatory mechanisms did not study ageing, as the tissue decline associated with ageing suggested a passive, entropic process of deterioration that occurred in a haphazard way. We know now, however, that the ageing process, like so many other biological processes, is subject to regulation by classical signalling pathways and transcription factors. Many of these pathways were first discovered in small, short-lived organisms such as yeast, worms and flies, but a remarkable fraction turn out to extend lifespan in mammals as well. In this article, I describe these pathways and their regulation by environmental and physiological signals. I also discuss unsolved mysteries in the field and, finally, the outlook for drugs that could slow ageing in humans.

Many people assume that extending lifespan by slowing ageing would mean certain death from, say, Alzheimer’s disease. Instead, we are finding that mutations that slow ageing also postpone age-related disease. This link raises the possibility of combating many diseases all at once by targeting ageing, their greatest risk factor. Fascinating as this topic is, age-related disease is not the focus of this article. Rather, its focus is ageing itself.”

The article goes on to discuss pathways that regulate ageing.

“We now know that the longevity response to dietary restriction is actively regulated by nutrient-sensing pathways involving the kinase target of rapamycin (TOR), AMP kinase, sirtuins and insulin/insulin-like growth factor (IGF-1) signalling. Unexpectedly, which nutrient sensor is most important in extending lifespan in response to dietary restriction depends on the way that dietary restriction is imposed. In C. elegans, for example, one nutrient sensor extends lifespan in response to life-long food limitation, another in response to every-other-day feeding and a third if dietary restriction begins in middle age.”

and notes

“Slowing ageing might seem like an overwhelming challenge, as the decline is so pervasive. So it is noteworthy that when we extend the lifespans of laboratory animals, we do not have to combat individually all the problems of age, such as the declining muscles, the wrinkled skin and the mutant mitochondria. Instead, we just tweak a regulatory gene, and the animal does the rest. In other words, animals have the latent potential to live much longer than they normally do.”

For the full text of the article, which is well worth reading, click here.

On the front page of the NY TIMES – August 19,2011 –Nicholas Wade reported on Dr. Rafael de Cabo’s newly published study on the positive effects of a resveratrol mimetic SRT-1720 on obese mice.  

To read the entire NY Times article by Nicholas Wade, click here.

I have followed this study, but I have also followed another one, linked and referred to in that article “the set back last year” – where in, George Vlasuk, Sirtris’ Chief Executive, announced that Sirtris had halted their resveratrol study. This story was also reported by Mr. Wade for the NY Times. 

What was striking, was that by discontinuing the study, an unspoken PR impression was created – namely, that resveratrol had failed or had been deemed to be ineffective. 

However, the interesting and significant thing here is that when you scratch the surface of the story, and see the facts as I have come to know them, the machinations behind the NY Times story become multi-fold – and curious. 

Last summer, I appeared with MIT’s Dr. Leonard Guarente on a number of radio programs and in interviews concerning his work in Sirtuin research and my film on the Science of Aging.  The subject of resveratrol came up a number of times.  Not only is Dr. Guarente a science advisor to Sirtris, the GlaxoSmithKline acquisition bringing forth the new SRT-1720 resveratrol mimetics, but he, at the time, was also an advisor to Dr. Sinclair and Dr. Westphal’s .org company, which in July 2010, was offering a Resveratrol formulation to the public.  The stated idea was to make this healthful compound available as a public service, in advance of any patentable mimetics, which carry the lag time of FDA approval.

 Soon afterward, GlaxSmithKline suspended resveratrol testing, and stopped Sinclair, Westphal, et. al., from continuing to sell resveratrol through their .org company. And soon after, the damaging article appeared. 

In that article referenced in Wade’s August 19^th piece, Sinclair actually disagreed with GlaxoSmithKline’s decisions about resveratrol and said so.  

Now, the positive results of a new patentable compound is reported upon. There is no direct mention of what happened with resveratrol. Sinclair is involved with the new study, everyone is upbeat. 

I have a certain perspective on the goings on behind the scenes. And this in turn highlights how the media reports on a subject, and how that methodology can lend itself to misinformation. 

For instance, in Wade’s article, he quotes Brian Kennedy, CEO of the Buck Institute, who strikes a cautionary tone at the end. It just so that I filmed an interview with Dr. Kennedy, in which he discussed getting calls from reporters like Mr. Wade, looking for opposing views.  The video gives insight into the media’s methodology. The clip can be viewed below.

The real story is the trajectory of the research.  Scientists will continue to attempt to disprove one another, that is the nature of the scientific process.  It is the pace of their advances that is striking.

On Sunday, July 31st, filmmaker Robert Kane Pappas was the featured
on The Staying Young Radio Show.
Robert was interviewed by Judy Gaman, along with Dr. Walter Gaman
and Dr. Mark Anderson on new breakthroughs in the science of aging.

The audio from the program The Science of Aging with Robert K. Pappas is attached here commercial-free [...]

One content note in the program for the David Sinclair/Bruce Yanker hosted aging Symposium certainly catches your attention. It’s the blurb at the bottom of Dr. Jonathan L. Tilly’s page outlining his presentation.

“Rewinding the Female Biological Clock for Fertility Reasons: An End to Menopause as Well?”

To me, this exemplifies the stunning hints of the deep human implications that aging research holds. How will society evolve when women are no longer driven by concerns about their biological clocks?

Behind these findings lies a recurring idea:

IT’S ALL ABOUT SIGNALING

Over the past several years, a number of scientists have recounted an experiment wherein researchers combined the bloodstreams of a young and an old mouse. Suddenly, the old mouse’s muscle tissues began to repair like a young mouse’s, that is, to act younger.

What this means is that the old cells are driven by their environment and retain the ability to become young again.  In the case of Tilly’s work, aged ovaries placed in a young environment became viable again,

 “based on his [Tilly] discovery of a population of stem cells in the ovaries of adult mice that are capable of generating new eggs”… “ovarian failure can be reversed through germline (egg) stem cell-based technologies.  He [Tilly] has also discovered a similar population of egg stem cells exists in humans.”

Another recurring motif in the scientific presentations could be phrased like this:  “We expected to see X but we were wrong.”  As I understand it, the reasons for the unexpected or contradictory results have to do with “Occam’s Razor.”  By this I mean that the results appear at first to be counter-intuitive.  But, as the scientists bore deeper into the mechanics of what is going on, the initial contradiction doesn’t hold.  Dr. Lenny Guarente explained this to me four years ago with glee. Scientists are trained to explore a question while making the fewest assumptions, which leads them to follow what appear to be logically predictive paths.  The point is, “Occam’s razor is not always correct.” This continual “reassessment” of what we assume to be true is the hallmark of aging research.

TO AGE OR NOT TO AGE will air on LINKTV this month beginning on Monday, June 20th at 11 am Pacific Time/2 pm Eastern Time.  

The airdates are as follows:

Monday, June 20th, 11:00 am PT/2:00 pm ET

Wednesday, June 22nd, 11:00 pm PT/2:00 am ET

Saturday, June 25th, 2:00 am PT/5:00 am ET

Saturday, June 25th,  3:00 pm PT/6:00 pm ET

LINKTV can been seen on DIRECTV Channel 375 and DISH Network Channel 9410.  For more information click here.

A video blog and brief comment by Robert Kane Pappas

The accompanying clip touches on the stages of a drug’s development. What struck me is that the journey from research lab to doctor’s office has so many intervening points.  Remember, that in our capitalistic system, a “discovery” will not come to market unless it can be monetized.  The financial stakes are huge. The process is fraught with PR.

Scientists have a bit of an inside joke amongst themselves. Whenever a member of the media asks how long it will be until a given discovery will be available to the general public, the stock answer is always “five to ten years.” That answer was repeated to me so often during filming that I finally ended up throwing it back at Dr. Guarente.

 The truth is that researchers don’t know how long, largely because of the FDA dance. I will comment further on this issue in a later segment.  One point worth mentioning; all the scientists that I spoke with seemed rather befuddled about the process whereby a drug gets approved. 

This blog entry focuses on a specific aspect of telomere biology, the epigenetic regulation of telomeres as mediated by TERRA, a recently-discovered RNA. Most popular discussions related to telomeres and telomerase are still based on simplistic earlier models of telomerase biology which do not take TERRA into account. So are the increasingly-popular commercial approaches to telomere lengthening via “telomerase activator” substances. The new TERRA-related research may explain how diet, certain supplements and lifestyle factors like exercise so profoundly affect telomere lengths and can inhibit cell senescence.

First, as a preamble or appetizer for what follows, regarding the relationship of telomere length and aging I invite you to view this 3-minute video featuring Dr. Nir Barzalai of the Einstein Institute for Aging Research.

Background on telomeres and telomerase.

Although this blog entry focuses on epigenetic regulation as a new and very important aspect of telomere biology, I continue to stand behind what I have written related to telomeres and telomerase reflecting a shift over a three-year period. The most-recent relevant blog entries were written in October 2010: Telomere lengths, Part 3: Selected current research on telomere-related signaling, telomere lengths, cancers and disease processes, Part2: lifestyle, dietary, and other factors associated with telomere shortening and lengthening, and Part1: telomere lengths, cancers and disease processes. These entries contain a great deal of information as well as links to multiple earlier blog entries on telomeres and telomerase. And, of course, the 12th theory of aging discussed in my treatise is Telomere Shortening and Damage. Three years ago, I thought that taking astragaloside IV or cycloastragenol supplements to extend telomeres was possibly a good anti-aging intervention. I no longer see that as the case.

In the abovementioned Part 3 blog entry I discussed how damaged or too-shortened telomeres can lead to epigenetic changes. “Another important contribution to the picture of how cell senescence affects aging is provided by the October 2010 publication Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. 

For a further scientific and technical discussion on the topic, click on the following link to the original post on Vince Guiliano’s blog, AgingSciences.com.

This video blog entry, like previous ones, is being brought to you in a close collaboration between  Vince Guiliano and Robert Kane Pappas.  They expect to generate several more of these blog entries which are structured around short video segments on aspects of longevity science.Vince is a longevity scientist who has for numerous years surveyed the emerging literature of aging science.  Vince writes perhaps the most popular blog in the field of aging science AgingSciences.com (formerly known as Anti-Aging Firewalls) where Vince analyzes and  synthesizes results from numerous disparate areas of research in terms of their implications for health and longevity.  The blog is very much the gold standard with over 350 postings, the majority of which are mini-treatises on topics of aging sciences.  Robert is the director of  TO AGE OR NOT TO AGE. Robert captured hundreds of hours of interesting video in shooting the film over a 4-year period, including extensive interviews with a number of prominent aging-science researchers.  It was possible to incorporate only a small fraction of that interesting material in the film itself.  However, Robert will be identifying short interesting segments of materials both in the film and not in the film, and Vince will be remarking on them just as in this blog entry. 

Last week, Vince Giuliano wrote a probing blog about aging and disease, which can be found on this site and on agingsciences.com.  I contributed a video clip. One of his underlying points is that a disease which is cured by stimulating one of these regulator genes — for instance SIRT1 or mTOR –- will likely result in increased lifespan as a side effect; so interrelated are aging, disease and mortality. The following clip extends this idea to ask, what are these genes doing?

Understanding these genes in terms of cellular repair and maintenance sheds light on:

1. Why people get differing degrees of a given disease. Why, for instance, one person gets MS, and in 5 years is confined to a wheel chair, while in another person, the disease plateaus and decades later that person is still functional.
2. Why some people get better, even as they are getting older.  They “successfully age,” meaning the body maintains or regains equilibrium, homeostasis.
3. When we age, many things are going wrong.  It seems to follow that a more sophisticated way of preventing and curing many diseases – especially those with multiple causes – would be to affect those underlying causes as a group simultaneously.
4. These genes help explain how some people are functional and active nearly up to their death; while others experience a long decline over decades.
5.  How some people handle the various stresses of life better than others. The word “stress” itself covers the gamut – there are environmental stresses, metabolic stresses, heavy metals, physical accidents, emotional and psychological trauma. These “insults” are dealt with on a cellular level. What’s more, they will necessarily also contain a neurological component.

There are unanswered questions concerning these regulator/repair genes, SIRT1, mTOR, and IGF-1.  How do they behave over time?  Does their activity decrease or increase?How much do their  activities overlap?

Everyone knows that old age can lead to many diseases and problems.  And sooner or later one of those diseases or problems will kill everybody.    But, what exactly is the relationship of aging to diseases?  The question leads to surprisingly interesting answers.

First, please have a look at this video for opinions of some prominent scientists:

Here, I address the points in the video and expand on several key related points. 

Aging increases the probability of multiple diseases and conditions which enhance the probability of death, and the rate of increase accelerates with age. 

Nobody dies of old age per-se but most everybody will die from a disease or problem of old age.  In the video Dr Guarante mentioned several disease susceptibilities that increase radically with aging including the biggies of cancer, heart disease, dementia and diabetes.  And there are many other conditions of aging that also lead to disability and death. For example, loss of eyesight and hearing can lead to automobile accidents.  Age related neurological and muscular changes can affect balance and body control leading to falls that create serious damage, disabilities and more imminent death.  Among trauma patients “Increasing age was associated with higher mortality, an increased proportion of falls and fatal head or spine injuries(ref).”

Increasing lifespans implies increasing healthspans.

Animal experiments with multiple species ranging from roundworms to fruit flys to mice indicate that interventions that radically increase lifespans have a similar effect on healthspans.  See, for example, the blog entry New extraordinary longevity lessons from the nematode which chronicles how researchers over 20 years have managed to discover interventions that multiply both the lifespans and healthspans of nematode worms (C-elegans) by a factor of over seven.

In humans the ratio of healthspans to lifespans has been historically increasing, not decreasing.    

We are not only evolving to live longer(ref)(ref) but also the proportion of our life spent in a healthy state is increasing.  This is the gist of the message in the 2004 publication CHANGES IN THE DISPARITIES IN CHRONIC DISEASE DURING THE COURSE OF THE TWENTIETH CENTURY by the Nobel-Prize winning economist Robert W. Fogel.  This fact is contrary to the fear that extending lives will lead to longer and longer periods of disability and skyrocketing medical costs. If this tendency were to continue long enough we could approach the state of the “One hoss shay” where most of us live full healthy active lives until one day we simply drop dead.  Personally, I intend to be one of those.

Interventions that increase our lifespans might be the most direct approach to addressing most diseases of old age.

The major diseases of aging occur in the biomolecular architecture or “remodeling” that occurs with advancing age in individuals on the organ, cellular, proteomic and epigenetic levels.  An age-related disease like Alzheimer’s Disease (AD) is not due to a bacterial bug that could be cured with any conceivable antibiotic.  Rather, the disease is associated with multiple and complex changes in gene expression, cells and tissues that go with aging.  So far, despite billions of dollars spent on research on AD, there is still nothing approaching being a cure.  See my May 2010 blog entry Alzheimer’s Disease research update.  (I am, by the way, currently working on an update reflecting the vast recent research efforts being devoted to AD.)

In animal models, an intervention that increases lifespan tends to postpone all of the disease susceptibilities and problems that occur with aging.  They still happen, but happen later.  This has led to a simple but powerful hypothesis:

The best way to get at most intractable diseases of aging is to go first after aging itself.   

Along with some highly respected researchers I very strongly suspect that if in fact a cure for AD is found, it will turn out also to be an anti-aging treatment.  Supportive of this point is the July 2010 publication SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10.  On the one hand “Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.”  On the other hand SIRT1 activation is activation of the calorie restriction pathway known to be life-extending for a wide variety of species.  I will say more about this particular research when I write next about AD research.  This research, incidentally, originated in Dr Guarante’s lab at MIT, the Glenn Laboratory for the Science of Aging.

Finding a cure to a single disease of old age may or may not by itself have a big effect on average lifespans. 

If such a cure addresses epigenetic factors related to aging, such a cure might indeed increase average lifespans(ref).  And I believe that for aging-related diseases, any approach to a cure that does not address the epigenetic factors is doomed to fail.  That is why I am optimistic that a good chunk of the $31.2 billion currently being spent by the NIH on medical research may turn out to be research on aging – even if it is now labeled as cancer, dementia or other research(ref). 

 Many of the current anti-aging interventions like use of Rapamycin were discovered accidentally, and I expect that pattern to continue.  Rapamycin was discovered from a random soil sample on Easter Island, an island known by locals as “Rapa Nui.”  That is how the drug got its name.  Later the mTOR gene was discovered because it was the gene that most reacted to rapamycin.  mTOR stands for “mammalian target of rapamycin.  And a little later yet it was discovered that inhibiting mTOR via rapamycin was life-extending across many species.  And now, rapamycin and the mTOR pathway are the subjects of intense research mainly addressed at curing diseases(ref).”  

I am willing to bet a healthy vegetarian dinner with anybody that if and as any disease treatment based on mTOR pathway inhibition emerges from the FDA approval gumball machine, that treatment will be life-extending.

 On the other hand, there are so many diseases and problems of old age that finding a cure for only one – say a specific cancer – is likely to affect average lifespan by only a few months unless that cure also addresses underlying processes of aging.  Replacing the fan belts in a 25 year-old car might keep the car running a while longer but all the other systems will be continuing to go downhill.

New anti-aging drugs will have to come on the market because they help treat or cure specific diseases.

This is because aging per-se is not regarded as a disease by the FDA and therefore drug approval cannot be based on anti-aging properties.  Besides, any clinical trial of a drug for anti-aging effects would have to go on 30 years or more and is therefore out of the question.  Our society and our institutions are simply not ready for us living much longer lives.  See the blog entry Getting the world ready for radical life extension.

Sirtris Pharmaceuticals, now a subsidiary of the drug company Glaxo Smith-Kline, may provide a model of how things will go for life-extending drugs.  “Sirtris is focused on discovering and developing proprietary, orally available, small molecule drugs with the potential to treat diseases associated with aging, such as Type 2 Diabetes. Our research focus is on modulating the sirtuins, a recently discovered class of enzymes involved in the aging process.”  The company currently has six clinical trials in its drug-development pipeline. 

I am willing to offer a second wager with anybody, again for a healthy vegetarian dinner.  My bet is that if and as any Sirtris disease treatment based on stimulating SIRT1 emerges from the FDA approval gumball machine, that treatment will be life-extending.

It is too bad that it is not possible now for anybody to develop, extensively test and market a drug simply because it is life-extending, but that is the name-of-the-game today.  That fact, however, may not turn out to be a major limitation because curing age-related diseases and life extension are so wrapped up with each other.

This video blog entry, like previous ones, is being brought to you in a close collaboration between  Vince Guiliano and Robert Kane Pappas.  They expect to generate several more of these blog entries which are structured around short video segments on aspects of longevity science.Vince is a longevity scientist who has for numerous years surveyed the emerging literature of aging science.  Vince writes perhaps the most popular blog in the field of aging science AgingSciences.com (formerly known as Anti-Aging Firewalls) where Vince analyzes and  synthesizes results from numerous disparate areas of research in terms of their implications for health and longevity.  The blog is very much the gold standard with over 350 postings, the majority of which are mini-treatises on topics of aging sciences.  Robert is the director of  TO AGE OR NOT TO AGE. Robert captured hundreds of hours of interesting video in shooting the film over a 4-year period, including extensive interviews with a number of prominent aging-science researchers.  It was possible to incorporate only a small fraction of that interesting material in the film itself.  However, Robert will be identifying short interesting segments of materials both in the film and not in the film, and Vince will be remarking on them just as in this blog entry.

This morning, Wednesday, March 9th, filmmaker Robert Kane Pappas was the featured guest of Joyce Riley on the Power Hour with Joyce Riley, a syndicated radio program available nationally and internationally.   Robert was joined by fellow collaborator, Vince Guiliano, for a lively two-hour discussion on longevity sciences and their implications. 

The audio from the program is attached here commercial-free (thanks to Terri Needham, our associate producer, who stripped out all the commercials) and can be heard by clicking on the following links.  The Power Hour (hour 1) and The Power Hour (hour 2).   To listen to the commercial-free version, you will need to download the program but it’s well worth the it to listen without advertising.   

The original program is commercially-supported and the program was interupted by numerous commercials, including ones for health products.  Neither Vince nor Robert endorse the products advertised. 

Vince writes perhaps the most popular blog in the field of aging science, agingsciences.com (formerly known as Anti-Aging Firewalls) where Vince analyzes and  synthesizes results from numerous disparate areas of research in terms of their implications for health and longevity.  The blog is very much the gold standard with over 350 postings, the majority of which are mini-treatises on topics of aging sciences.  Click here to read Vince’s own reflections on appearing on The Power Hour.