Aubrey & Me

Aubrey & Me

I’ve been in the field of aging research from the late 1990s, just the time when Aubrey de Grey was getting his start.  Before others, Aubrey had the vision to realize that cancer, heart disease, and Alzheimer’s would never be conquered without addressing their biggest risk factor: aging.

From the beginning, I admired Aubrey’s successes in communicating with scholars and the public, and I reached out to him.  He has always been gracious and supportive of me personally, appreciating the large common ground that we share. There is, however, one foundational issue on which we disagreed from the start.

Aubrey regards aging as an accumulation of damage.  Evolution has permitted the damage to accumulate at late ages because (as Medawar theorized in 1952) there is little or no selection against it, since almost no animals live long enough in the wild to die of old age.  Aubrey’s program is called SENS, where the E stands for “engineering.”   The idea is to engineer fixes to the 7 major areas where things fall apart with age.

I regard aging as a programmed process, rooted in gene expression.  Just as we express growth genes when we are in the womb and ramp up the sex hormones when we reach puberty, so the process continues to a phase of self-destruction.  In later life, we over-express genes for inflammation and cell suicide; we under-express genes for antioxidants, autophagy (recycling), and repair of biomolecules.  I believe in an approach to anti-aging that works through the body’s signaling environment.  If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young.  The body is perfectly capable of doing its own repair, and needs no engineering from us.

Over the years, research findings have accumulated, and both Aubrey and I have learned a thing or two.  I’m happy to say that our favored strategies are converging, even as our philosophical underpinnings continue to differ.


A unifying idea in my research has been that aging is an evolved adaptation.  This is a statement about evolutionary biology, but I came to it before I studied evolution, by looking at the phenomenology and genetics of aging.

  • The body does not appear to be doing its best to stay young.  We can see this because when the body is under stress, it has less available resources, but manages to a better job of protecting us from aging damage.  This phenomenon is called hormesis.
  • There are single genes that can be disabled, greatly extending lifespan in worms. Some of these have no known detrimental side-effects (pleiotropy).  These could only have persisted in the genome if natural selection is favoring aging for its own sake.  Similar genes exist in higher organisms, though their effects on lifespan are not as dramatic as the 10-fold increase in worms’ life expectancy in worms that comes from eliminating both copies of AGE-1.
  • Most genes that affect the rate of aging have been around for a long time, and do the same job.  This means they are evolutionarily conserved. For example, insulin is the most effective modulator of aging in mammals (including humans).  In higher animals, insulin is secreted by the pancreas, from whence it regulates blood sugar and fat storage. But yeast cells existed half a billion years before the first mammals, and have no pancreas, as my friend Barja has pointed out; and yet insulin was already a primary modulator of aging in yeast.Article Image

Programmed aging and optimism

There was a time when I spoke of “aging genes” and looked for drugs that could jam their targets and turn the genes off.  Meanwhile, the science of epigenetics, or gene expression, was coming of age, so to speak. We learned that genes are turned on and off, not just in different tissues, but at different times of life.  I came to think less in terms of “aging genes”, more about multipurpose genes that are deployed in appropriate combinations when we are young, keeping us strong and healthy. But as we get older, the proportions change.  Aging is not accomplished via new mechanisms of self-destruction, which evolution invented for that purpose. Rather, the proportions are re-shuffled and change gradually, with effects that are more and more detrimental over time.

  • For example, the immune system is vital for protecting the body, but it becomes indiscriminate with age. In older people, the immune system fails to protect us from microbial infections, and simultaneously, immunity turns against the self.  Autoimmunity contributes to arthritis and to Type 2 Diabetes (metabolic syndrome), as well as playing a role in AD.
  • For example, p53 is a gene that promotes apoptosis, or cell suicide.  We need for cells to be smart enough to destroy themselves when they are infected with a virus or if they are cancerous.  But later in life, apoptosis is on a hair trigger, and we lose muscle and nerve cells that are still healthy and functional.
  • For example, inflammation is used as a primary defense against microbes, and a way to eliminate tissue around a wound so that it can be replaced; but as we get older, signals that promote inflammation are dialed up higher and higher.  Chronic inflammation contributes importantly to all the diseases of old age.

Twenty years ago, I imagined one or a few medications that would block the effects of aging genes.  I wrote that the thesis of programmed aging implied great optimism about the ease with which aging might be combatted.  I thought that merely lengthening telomeres might add many years to our lifespan.

Ten years ago, I saw that what was needed was re-balancing of signaling molecules to create a more youthful environment.  My hope was that a few transcription factors (master regulator genes) might control a large number of signal molecules and we might set the clock by controlling just a handful of master signals.

More recently, I have come to realize that shortening telomeres are only a small part of the aging program.  Worse, there is no clear line between transcription factors and hormones. Most hormones affect transcription, and most transcription factors have direct metabolic effects.  There are thousands of transcription factors in the human genome.  As a result, my robust optimism has been tempered, and I have come to think that we need to look for ways to re-balance a great number of genes to effect rejuvenation.  I still believe in a signaling approach, but I see signals as a tangled web of cause and effect, in which every cause is also an effect, and every effect has a side-effect.  Modulation of the signaling system toward a more youthful state is possible, but not easy.

Aubrey’s program, too, has changed over time

Aubrey has never believed that aging evolved as a program, but rather that aging is a manifestation of damage that is permitted to accumulate because of evolutionary neglect.  Recently, he has argued explicitly against the idea of programmed aging, not for the reasons that traditional evolutionists offer, but by an argument that is uniquely his own.  In his words, “it is impossible for a species to maintain two sets of genetic pathways whose selected actions diametrically oppose each other. Specifically, since we clearly have a great deal of anti-aging machinery…we cannot also have pro-aging machinery.”  (My response is that we have pro-aging and anti-aging machinery that are activated at different times of life.–see Aubrey’s comment below.)

Over two decades, Aubrey, too has paid attention to research results, and his thinking about what is necessary to achieve rejuvenation is changing.  I see changes in the combinations of signal molecules and call it an evolved program. Aubrey sees the same thing and calls it “dysregulation”, which is a kind of damage.  Aubrey and I agree that re-balancing of hormones and other signal molecules is going to be essential.

Aubrey now finds optimism in the existence of what he calls “cross-talk”.  If we engineer a fix for one kind of damage, the body may sometimes regain the ability to repair other, seemingly unrelated kinds of damage.  Hence, we may not have to engineer solutions to everything—some will come for free. A dramatic example is in the benefit of senolytics. Cells become senescent over time.  I see this as a programmed consequence of short telomeres; Aubrey sees it as a response to damage in the cells. But both of us were surprised and delighted to learn, a few years ago, that elimination of senescent cells in mice had 20-30% benefits for lifespan.  Even though only a tiny fraction of all cells become senescent, they are a major source of cytokines (signal molecules) that promote inflammation and can cause nearby cells to become senescent in a vicious circle; this apparently accounts for the great benefit that comes from eliminating them.  If we find appropriately selective senolytic agents that can eliminate senescent cells without collateral damage, then the signals that up-regulate inflammation will be cut way back, and a great deal of the work needed to repair inflammatory damage is obviated.

The SENS 7

The SENS web site still lists the same 7 categories of damage that Aubrey has used for many years.  But the program to address these 7 has shifted a bit from bioengineering of exogenous solutions to signaling approaches that support the body’s innate mechanisms (which we know are sufficient to keep the body in good repair through several decades of early life).  For eliminating the plaques associated with AD, SENS at one time favored the engineering of artificial antibodies that would attack them, but more recently they see promise in the discovery of Dr. Sudhir Paul that our bodies already have catalytic antibodies, each capable of destroying many antibodies and re-cycling itself for the next one.  Where once Aubrey saw the need for tissue engineering to replace worn-out body parts, he now sees promise in reprogramming somatic cells to become stem cells, so that our bodies can regenerate damaged tissues endogenously.  Aubrey’s 1999 dissertation in biochemistry was about the theory that aging was caused by the damage inflicted by free radicals generated in our mitochondria, but he has long since embraced the fact that free radicals have an important role as signal molecules, so that anti-oxidants are not helpful for anti-aging.

Dr Aubrey de Grey presents a Director's Colloquium to the NASA Ames Research Center staff entitled 'Prospects for defeating aging altogether' Dr. de Grey is a British bomedical gerontologist educated at Cambridge University in the UK. A video of the presentation is currently available at the NASA Ames Library.

Aging is not the only threat to human life

One respect in which my thinking has always departed from Aubrey’s is that I see humans as part of a continuous web of life on earth, integrated into a global ecosystem.  Aubrey doesn’t worry about the Sixth Extinction that human activity has initiated because he anticipates that future humans will invent ways to support future human life as necessary.  I value nature for its own sake, and I also believe that human life depends on ecoystem support in ways for which we have seen hints, but that we have not yet begun to study. Aubrey draws a sharp line between the value of human life and the value of other life, and he is highly optimistic about the ability of our species to find new ways to sustain ourselves in a post-ecologic world.

 

The Bottom Line

In my youthful enthusiasm, I was entirely too optimistic about the prospects for near-term anti-aging fixes.  Aubrey was probably too conservative about the scope of what needed to be done to generate man-made solutions for problems the body can’t solve itself.  I have come to understand the complexity of the body’s signaling network, and the fact that it is inseparable from cellular metabolism. Aubrey has come to realize that the body has endogenous solutions that can be activated more easily than we can engineer substitutes for them.  I’ve been moving the timeline out, as he has been moving the timeline in, and there is much that we agree about.

I’m grateful to Aubrey — we all are — for the energy, the expertise, and the humor that he has brought to his chosen role, as a public advocate for bringing anti-aging strategies into the mainstream of medical research.

 

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Updated: November 20, 2018 — 3:59 pm
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