Dear Readers –
It’s been a deeply gratifying year for me. Twenty years ago, I first started writing that aging is something the body does to itself, a body function, rather than deterioration or loss of function. Journals would not even send my submission out for peer review. Journal of Theoretical Biology sent me the considered opinion of their anonymous reviewer, “JTB shouldn’t touch this topic with a ten-foot pole.” The conflict with prevailling evolutionary theory was just too deep.
But in the interim, the evidence has continued to pile up, and many medical researchers have taken the message to heart in a practical way, setting aside the evolutionary question and just pursuing approaches that seem to work. The most promising developments in anti-aging medicine involve changing the signaling environment rather than trying to “fix what goes wrong” with the body.
“First they ignore you…
then they laugh at you…
then they fight you…
then you win.”
The paradigm of programmed aging passed this year from stage 2 to stage 3, with prominent articles arguing against the possibility of programmed aging [Kirkwood, de Grey, Vijg & Kennedy]. Current Aging Sciences devoted a full issue to the question. I welcome the discussion. This is a debate that colleagues and I have sought to initiate for many years. There are powerful theoretical arguments on one side, and diverse empirical observations on the other. The scientific community will eventually opt for empiricism, but not until theory digs in its heels and fights to the death. A basic principle of evolution is at stake, and many theorists will rise to defend the basis of their life work; but a re-evaluation of basic evolutionary theory is long overdue.
The idea that fitness consists in reproducing as fast as possible is no longer tenable. For plants, this may be approximately true. But animal populations cannot afford to reproduce at a pace faster than the base of their food chain can support. Animals that exploit their food supply unsustainably will starve their own children, and there is no evolutionary future in that. This is a principle that links together entire ecologies, and the foundation of evolutionary theory will have to be rewritten to take it into account.
The Programmed Aging Paradigm: Is it a Cause for Optimism in the Quest for Extended Human Life?
For many years, I put forward the argument that programmed aging means there are genes that serve no other purpose than to hasten our death, and that medical research should be targeting the products of those genes. (Once a pathway has been identified, pharmaceutical science knows well how to block it with engineered drugs, like beta blockers and MAO inhibitors and serotonin re-uptake inhibitors.)
But in recent years, epigenetics has eclipsed genetics as the major theme in molecular biology. Everything that happens in the body is determined by which genes are expressed where and when. The vast majority of our DNA is devoted not to coding of proteins but to promoter and repressor regions that control gene expression with exquisite subtlety.
There has been a growing recognition of aging as an epigenetic program. As we get older, genes that protect us are dialed down, and genes for inflammation and apoptosis are dialed up so high that healthy tissue is being destroyed. Many epigenetic scientists have discovered this, and they find it natural to see aging as a programmed phenomenon. (Most have never been to graduate courses in evolutionary science, where they would have been indoctrinated into the perspective of the selfish gene.)
At first blush, it seems that an epigenetic program is just as amenable to pharmaceutical intervention as a genetic program. A few years ago, I wrote about transcription factors as the key to aging. Transcription factors bind to DNA and turn whole suites of genes on and off in a coordinated way. If we can restore a youthful transcription environment in an older animal or human, the body knows how to repair damage and re-create a younger self. The model I had in mind was based on a small number of powerful transcription factors controlling expression of a much larger number of genes, controlling a yet larger population of metabolites.
This summer, I had a chance to work in a worm genetics lab and consult closely with people who know the experimental details. I learned that there is no clear line between functional proteins and transcription factors, that many proteins have multiple functions, and that metabolites feed back to control gene expression. Instead of a pyramid, I should think of a web of causes and effects.
The entire system is primed for homeostasis, meaning that it responds to any intervention, seeking to move the system back toward its previous state. Of course, it is this capacity for recovery that makes life robust; but it also means that there is no “command central” which can be tweaked to move the whole system at once toward a desired state.
I still believe that there are one or more aging clocks that inform the body of an age-appropriate metabolic state, and synchronize the aging of different systems. Telomere length is one such clock. If we can reset an aging clock, the body will repair and clean itself up. If we can reset several clocks, the body may be able to restore itself to a younger state. But I recognize the possibility that the clock is diffused through the detailed epigenetic status of a trillion cells, and may be beyond the reach of foreseeable technology.
A few years ago, Steve Horvath of UCLA gave us the most explicit picture of an aging clock. He found it in one particular epigenetic marker: the pattern of DNA methylation. The Horvath clock is distributed over 353 sites. This is a clock that can be read for any given cell, but can it be changed or adjusted in each of the body’s trillions of cells? The prospect is daunting, and we do not yet know how to go about it. 2016 saw the first use of CRISPR technology for therapy in a living human. CRISPR could, in principle, be used to alter gene expression, one gene at a time. To re-regulate the expression of 353 genes in one treatment would probably require new concepts and new discoveries.
Short of resetting the aging clock, there are several technologies just over the horizon that should offer substantial life extension benefit. I believe the best prospects are senolytics (ridding the body of senescent cells), telomerase activators (rejuvenating old stem cells), and adjusting blood levels of key hormones and cytokines that increase or decrease with age.
The Bottom Line
Programmed aging is the right model to keep in mind as we search for interventions that slow the aging process and lessen the incidence of heart disease, cancer and Alzheimer’s all at once. Prospects are good for real breakthroughs, perhaps as soon as 2017, but I am no longer as optimistic as I was just a few years ago that complete rejuvenation is on the horizon.
Wishing you health and vitality for the coming year,
– Josh Mitteldorf