The Mystery of Aging, Solved at Last!

How many headlines have you seen that purport to reveal THE secret of aging?  Just in the last few weeks,  there have been several fundamental, earthshaking, paradigm-shifting, game-changing, disruptive discoveries–and they were very different one from another.

Why do these headlines keep popping up?  Is there truth in any of them?  …and, most interesting to me, What is it that they are all missing?

I’m a culprit in this game, too.  My publisher wants to call my forthcoming book Cracking the Aging Code.

I’m going to cover seven of these news releases below; I trust you’ll let me know if you want to hear more about any of them in particular.

What to Eat while FastingI have posted a page of recipes for my variation on Longo’s Fasting-Mimicking Diet.  These recipes are not endorsed by Dr Longo, but they have the same profile of macronutrients (calories, protein, fats, carbohydrates) as the products soon to be available from L-Nutra.

These recipes are based on fresh foods, and the fiber content is much higher than the FMD that Dr Longo has tested.  Intuition tells me that fiber can only add benefit, but this is untested.

Delay of Aging by Remote Control

“UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems.”  [Science Daily from last fall]

AMP Kinase is a key chemical workhouse for energy production and regulation.  In this study, the AMPK gene in fruit flies was found to be a signal that controls autophagy throughout the body.  (Background: Autophagy is recycling at the cellular level.  It declines through the life span, with the result that molecular gunk accumulates and production of properly-formed proteins declines.)

Life span and health span of the flies were increased when the gene for AMPK was activated in the nervous system, and independently in the digestive system.

 

Role of Mitochondrial Damage vs Epigenetics

Jun-ichi Hayashi of Tsukuba University was an early enthusiast of the mitochondrial free radical theory of aging, who became convinced by his own lab results that the theory doesn’t work.

Background: Mitochondria are thousands of organelles inside a cell that burn sugar for electrochemical energy that the cell can use.  They have their own DNA and their own reproductive cycles within a cell.  They generate reactive oxygen species (ROS) as a byproduct, and it was an attractive theory to attribute aging to damage and mutations they suffer because they are at ground zero for high concentrations of ROS.

Over the last two decades, we have learned that mitochondria do indeed play a central role in aging, but the story is not about simple damage.  In his latest paper [research article, Science Daily report], researchers from Hayashi’s lab show that there is no difference in the amount of DNA damage in mitochondria from cells of young people and from old people.  Why then do mitochondria perform less well, and provide less energy in older people?  They go on to propose that it is the epigenetic programming (in the cell nucleus, not the mitochondria) that makes the difference, and they identified two genes (GCAT and SHMT2)  that may be all that is needed to restore youthful function to the mitochondria.  These genes control production of glycine, the simplest of the 20 amino acids that are common protein constitutents.  Simply feeding the cells with glycine also improved mitochondrial function.  (You can buy glycine tablets as a supplement, but the body already has a lot, so it’s a good guess you would need a lot of it to make a difference.  Food sources rich in glycine include gelatin, shrimp, spirulina, and raw ostrich meat.)

 

Simple Flip of a Genetic Switch

Johnathan Labbadia at Northwestern University has discovered an epigenetic switch, a set of genes that is turned on that begins the aging process in lab worms [Research article from the Morimoto lab, Science Daily summary].  Worms begin aging at the tender age of 3 days, just a few hours after adulthood, with a switch that represses Heat Shock Protein.  HSP is not jus for heat, but a high-level signal that invokes a set of responses that create resiliency in response to stress of many kinds.  In worms and in other animals, stress resistance is closely associated with longevity, and HSP is associated with longer life span in worms [ref].

Scientists who see aging as a purposeful, programmed event, myself included, look to mechanisms of epigenetic control, as we are hopeful that signaling can be modified to avert aging.  But traditional evolutionary biology denies that there can be such direct control of aging.  According to theory, such switches could only be flipped if flipping them increased reproduction in a way that more than offsets the loss of reproductive opportunity from aging.  In keeping with the standard theories, Labbadia and Morimoto, looked for a connection to reproduction in the epigenetic switch they discovered.  They found one, but–undermining the theory–they found that the benefits for reproduction and the costs in the form of aging could be easily separated.

“In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.”

Why doesn’t the worm do this, and get the best of both?  Must be some kind of mistake, the Northwestern team asserts.  “Dysregulation” has become a favorite word, though many have enough integrity and insight to be scratching their heads, wondering why there should be so much “dysregulation” involved in aging, when we rarely find anything else about the metabolism that is consistently dysregulated.

 

Older Blood Vessels are Better Protected against Oxidative Stress

This press release from University of Missouri descirbes evidence that cells of the arterial lining (epithelium) are more resistant to oxidative damage when they are older.  Research from the lab of Steven Segal used hydrogen peroxide (H2O2) as a stressor.  Peroxide is also known to be a multi-purpose signal molecule that can induce cell suicide (apotosis) in high concentrations, and can induce protective anti-aging response at lower levels [ref, ref].

The article is framed within an old and discredited view of that regards aging as a simple result of oxidative damage [ref].

Although the causes of many age-related diseases remain unknown, oxidative stress is thought to be the main culprit. Oxidative stress has been linked to cardiovascular and neurodegenerative diseases including diabetes, hypertension and age-related cancers.

It should no longer surprise us that anti-oxidants are not anti-aging [ref], or that pro-oxidants can be anti-aging [ref], or that aging is an active process controlled by central signals, not a passive process of damage [ref].

 

Getting to the Bottom of Aging

This article claims to find the root of aging at the cellular level.  In particular, it is in the endoplastic reticulum [background in a Kahn video]. The ER is a transport network inside the cell that directs each protein molecule to a targeted location.  It does more than this–it finishes and folds the protein after it is manufactured.  The new study finds differences between the ER of old and young cells, studied in lab worms and in cultured human cells.  [Here is a Science Daily summary.]  Proteins tend to be misformed and misfolded by the ER of old cells..

In direct contrast to the article just above on blood vessels (“oxidative stress is thought to be the main culprit” ), the claim here is that there is not enough oxidation in the ER of old cells.  It is the reduced state of the ER that is responsible for misfolding of proteins.

 

Diverging Paths from Parabiosis Experiments:  GDF11 and TGF-β

In the early 2000s, Irina Conboy and Amy Wagers were grad students in Tom Rando’s Stanford University lab, studying parabiosis in mice.  They learned that tissues in an old mouse could be rejuvenated by exchanging blood plasma with a young mouse.

Blood plasma is the liquid, containing dissolved signal molecules but no whole blood cells, no stem cells.  The implication was that the old tissues could receive instructions from other parts of the body (an epigenetic clock?) causing them to get older or to revert to a younger state.

Following up on this work: Now Irina and her husband Mike Conboy have a lab at UC Berkeley, where they are focusing on TGF-β as one of the signals that causes aging.  They are experimenting with a drug that blocks TGF-β receptor, and found that it has rejuvenating effects both on muscle and brain cells [press release, research article].  The implication is that excessive TGF-β in the blood is a source of aging.

Wagers is at the Harvard Stem Cell Center, where her biggest trophy so far is the discovery that GDF11 has rejuvenating effects in muscle and nerve cells.  The implication is that there is not enough GDF11 in the blood in the blood of older mammals, and this is a source of aging.

The irony is that GDF11 is a form of TGF-β.  The findings of Wagers and Conboy have diverged to the point where they have focused on the same signal as pro-aging (Conboy) and anti-aging (Wagers).

I don’t have the expertise to take sides in this disagreement, but others have noted that Wagers’s claim seems counter-intuitive. Doubts were expressed about Wagers’s findings by researchers at Novartis (a Cambridge, MA pharmaceutical lab), where David Glass claims he has been unable to duplicate Wagers’s work, and that in his experiments with mice, GDF11 seems to decline with age.

Wikipedia says, “GDF11 is a myostatin-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin.” [emphasis added].  Myostatin is an inhibitor of muscle growth whose structure is 90% homologous to GDF11.

Images of cells in the brain’s hippocampus show that the growth factor TGF-beta1 (stained red) is barely present in young tissue but ubiquitous in old tissue, where it suppresses stem cell regeneration and contributes to aging.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”

 

Keeping your Brain Active with Balance Exercises

A pilot study by Ross and Tracy Alloway of Univ North Florida suggests that balance exercises improve working memory and protect against neurodegenerative disease. [UNF press release]  The focus of the study is termed “proprioception”, awareness of body position.

We all lose brain cells with age, and I think of Alzheimer’s dementia as one end of a spectrum.  Some herbs have been studied for neuroprotective effects.  Vigorous exercise is neuroprotective.

In parallel to my life as a scientist, I have always practiced yoga and I have taught one yoga class each week for almost 40 years.  Balance exercises are an essential aspect of yoga.  Intuition tells me there is an anti-aging benefit in yoga practice, and there is implicit evidence for this.  I think the connection between yoga and aging deserves a lot more study, but of course it cannot be done with animals, and blinded, controlled experiments are not feasible.

22 thoughts on “The Mystery of Aging, Solved at Last!

  1. I have talked to Michael and Irina at length about their work and there was no way GDF-11 was going to work. I take Creatine to inhibit Myostatin build up so for me the Wagers data just didn’t make sense and is not consistent with the other experiments.

    TGF-β is a big player in aging and it causes levels of B2M to rise too which has recently been in the news too as that inhibits neurogenesis. Again another offshoot of the original Conboy work and parabiosis and it further vindicates what Irina has said. B2M levels in her experiment fall to near youthful levels once TGF-β is inhibited thus it is a two birds with one stone thing and validates the Conboy work.

    http://news.sciencemag.org/biology/2015/07/old-age-protein-may-cause-memory-loss

    I would love for you to do an article about their work and Michael and Irina I suspect would enjoy the publicity, they are close to some practical uses for their work and frankly could use the exposure.

    In general terms Newcastle UK released a study confirming that good telomeres get you to your 90s and beyond that inflamation and genes determine if you live into the 100s. No real surprise so lets rejuvenate the telomeres and see what we shall see!

    http://www.ncl.ac.uk/press.office/press.release/item/scientists-crack-the-secret-of-the-centenarians

  2. Having read the SENS Question of the month regarding mitochondrial mutations, I feel a bit uneasy about your conclusions based on the glycine-mitochondria study. Do read their entire reply regarding that study:
    http://www.sens.org/research/research-blog/question-month-11-are-mitochondrial-mutations-really-all-important

    “For these reasons, it’s long been understood by biogerontologists that to unravel the drivers and effects of degenerative aging, scientists must study the cells and tissues of animals that have completed childhood and adolescent development. It is not merely premature, but unsound from first principles, to conduct studies in rapidly-dividing cells undergoing dramatic, regulated epigenetic changes, and draw lessons from them regarding what happens to aging cells in tissues that either don’t divide at all, or divide much more slowly, and that are long past their developmental period. Unfortunately, this understanding has been underappreciated by scientists from non-biogerontology specializations, leading to many studies being designed and interpreted inappropriately for purposes of understanding and intervening in degenerative aging.”

    • The thing is, that there appear to be quality control mechanisms that ensure dysfunctional mitochondria are eliminated.

      “Thus, suggesting that mitochondrial dysfunction is a good enough reason for eliminating mitochondria and as Dr. Skulachev says, mitochondria follow the samurai’s law; “it’s better to die than to be wrong”.”-Mitoptosis, a Novel Mitochondrial Death Mechanism Leading Predominantly to Activation of Autophagy, 2012

      We already have the sequences of animals(bowhead whale) that appear to live for multiple centuries, and that according to some do not even appear to age. As far as I know, I’ve not heard of evidence of mitosens like solutions having evolved to allow such extreme longevity. Even in mammals, afaik, humans do not have further mitochondria genes transferred to the nucleus compared to shorter lived species like bonobos or mice, the solution to extend lifespan proposed in mitosens, iirc.

      For all we know the only reason mitochondria dysfunction might occur is either inheritance of sufficient mutation load from parents or age related downregulation of quality control mechanisms.

  3. Hello Josh. 22 years old here, and following your blog with enthusiasm. Keep the good job !

    I got interested in health and longevity in my late teen years, first with vitamin D and sleep hygien. Now I exercice daily, eat tons of vegetables, olive oil, blueberries, nuts and so, and take a great deal of supplements like metacurcumin, resveratrol, ashwagandha, green tea, and other.

    I’m young looking, peole often think I’m 16-17, which suggest I have good genes (my parents also look younger).
    Can I expect to keep a young body for very long ?

    • Hi, Fabien –
      Congratulations on thinking with foresight about your health. My advise is to continue respecting your body, learning what helps you feel strong and function at your peak. But don’t worry overmuch about longevity. In coming decades, I think that science will offer you treatments and tools for longevity that make the long-term effects of your present behavior relatively unimportant.
      – Josh

    • Hi Fabien, You are doing good. The only thing I would suggest is that you also take a 1,000 mgs timed release tablet of vitamin C once a day, and take up weight lifting, and jogging. Good luck!

      • Hey Jerry and thanks for your reply.
        I prefer vitamin C mostly from food rather that from supplements. I sometimes take 250mg only.

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