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Open Letter on Research Priorities in Aging

cynthia kenyonLast week, I had the honor of speaking with Cynthia Kenyon, who has been recruited by Google to direct research activities at their new venture into aging medicine, called CALICO, for California Life Co.  She was kind enough to listen to my thoughts on research priorities seeking near-term breakthroughs in human life extension.  Here is what I said to her, paraphrased with some added background and comments.


It is my belief that the timing of development and aging is determined by chromatin* state.  The body knows how to be young, and it knows how to be old.  The difference is coded in chromosomes, especially in telomere length of stem cells and epigenetic markers in endocrine cells.

* Chromatin is the DNA in the cell nucleus, together with the histone spools around which it is wrapped and all the proteins and side-groups that are loosely and temporarily attached.  Spooled DNA is called “heterochromatin” and it is mostly silent.  Unspooled DNA is termed “euchromatin” and it is more likely to be active.  All the protein markers, the methyl groups and acetyl groups strategically placed, together determine when and where particular genes are expressed.  This phenomenon is called “epigenetics”.  How is epigenetic programming effected?  The cell’s epigenetic language if much more complex than the Genetic Code, and is yet poorly understood.

I am proposing that aging is, in large part, a matter of epigenetics.  A different set of genes is turned on when we are young compared to when we are old, and that makes all the difference.  Here are four references on the subject, including my own #4 [Ref1, Ref2, Ref3, Ref4].

 

Background assumptions

I believe that aging is controlled by several biological clocks.  This is a strong claim, but I think it has good support, outlined in the references above.  Biological clocks certainly control development, puberty and related schedules early in life.  How the body knows its own age is yet incompletely understood.  It’s a good bet that the same clocks that control development have been re-purposed to control aging.

There are three clocks we know something about.  These are the epigenetic clock, cellular senescence (telomere loss), and life-long shrinkage of the thymus, master gland of the immune system.

A common way to construct a clock is with a feedback loop.  A clock looks at itself to determine its next move.  The body has a feedback loop between epigenetic state (at a cell level) and circulating hormones and RNAs (at a systemic level).

  • The epigenetic state determines which hormones and RNAs are expressed.  Endocrine glands in particular are sending hormones out into the blood which are selected by their epigenetic state.
  • The circulating hormones feed back to cells and re-program the epigenetic state. All cells in the body are constantly receiving signals from the blood that guide them in continually reprogramming their DNA to express some genes and silence others.

There is evidence that telomere length in stem cells constitutes an independent aging clock.  Studies have shown that people (and other mammals and birds) with shorter telomeres have shorter life expectancies than people with longer telomeres.  Extending telomere length is simply a matter of signaling the body to express telomerase, which is always available in the genome but normally is expressed only in embryos.

The thymus is the organ where white blood cells are trained to attack foreign invaders and lay off the body’s own cells.  The thymus shrinks beginning in childhood, accelerating with age.  Late in life, the thymus becomes seriously deficient in its function, with the result that white blood cells make two kinds of mistakes.  Type I errors cause the T-cells to fail to attack invading parasites, with the result that we get sick more often as we age.  Type II errors cause the T-cells to attack healthy cells, leading to the auto-immune diseases of late life such as arthritis and exacerbating inflammatory damage.

 

Strategy

 1) There is intriguing data from parabiosis that circulating factors may be able to reprogram the body’s age state.  (This is the “back end” of the feedback loop described above.)  If we’re looking for quick progress against aging, the circulating hormones are more accessible and make a more convenient target than trying to get inside the cell nucleus to reprogram epigenetic state directly.

Some of the blood factors most important for aging have already been identified.  For example, as we get older, we have too much NFkB, too much TGF-ß.  We have too little GDF11, too little oxytocin.  Irina Conboy has led me to believe she knows a few more, and identifying these factors is at the center of her research.  It’s a good bet that Tom Rando,Amy Wagers and other parabiosis researchers are compiling their own lists.

If we’re lucky, then adding some factors to the blood while blocking others will have a long-lasting effect of re-programming epigenetics, and the body will take over by continuing to secrete a “young mix” into the blood stream.  If we’re not so lucky, it may be necessary to perform some epigenetic re-programming more invasively.  CRISPR technology holds promise in this regard.

2) I believe that telomeres will also have to be extended in a fully-effective anti-aging program. Many herbs and supplements are known to have small activity in promoting telomerase (e.g., cycloastragenol, silymarin, carnosine).  Bill Andrews claims to have a synthetic telomerase promoter that is 50 times more potent than any of these.  Mike Fossel and others are also pursuing the search for telomerase activators.

3) Multiple treatments have been documented over the years to increase thymus size in humans and in animals.  These include growth hormone, zinc, melatonin, and thymic peptides.  A recent breakthrough from Univ of Edinburgh suggests a particularly effective treatment.

 

Roadmap

Telomerase activators are ready for safety tests and human trials now.

Various techniques for thymus regrowth are ready for clinical trials.

Based on encouraging results with mice just last spring, Tony Wyss-Coray of Stanford Med School has just begun human trials (for Alzheimer’s Disease).  This work should be rapidly expanded if his preliminary results are promising.

GDF11, oxytocin and other blood factors should be tested for rejuvenating potential in rodents.  Drugs can be developed that block NFkB and other pro-inflammatory signals.

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This article originally appeared on Josh’s excellent Aging Matters blog here.