Today I'll point out a view of the divide between theories of programmed aging and non-programmed aging, written by one of the more prominent programmed aging theorists in our community. I think it matters deeply as to whether we are guided by the theory that aging is caused by accumulated damage, or whether we are guided by the theory that aging is caused by an evolved program that is actively selected for. Is aging a matter of damage causing epigenetic change and cell dysfunction or a matter of epigenetic change causing damage and cell dysfunction?
This is an important division in the research community. The strategies for treating aging that must be proposed, agreed upon, and funded in well in advance of any evidence of effectiveness are very different in either case, and there is no reason to believe that the strategies of the wrong camp will prove to be useful. This is because addressing root causes is a powerful way to produce sizable gains, removing many downstream problems. Addressing downstream problems, on the other hand, has very limited utility: it is much harder, the benefits are much smaller, and the root causes will continue to cause a range of other harms. One side of this debate is wrong, and their proposed therapies will largely be a waste of time and energy, producing only marginal benefits at the end of the day.
Why can't we just determine who is right and who is wrong from an inspection of what is known of aging to date? Well, arguably we can, or at least form strong opinions about it, but there is nonetheless sufficient room for debate. The majority consensus is that programmed aging is an incorrect interpretation of the evidence, but the programming aging community is thriving nonetheless. Aging is complex and poorly understood in the details of its progression, and this is because cellular metabolism is complex and poorly understood. There is a great deal of latitude to argue about which correlated metrics in aging are cause and which are effect when it comes to the inner details of cell behavior, molecular damage, tissue function, and so forth. So given the very same data and evidence as a starting point, for much of aging it is still possible for programmed aging theorists to argue that epigenetic changes are the root cause, and for the rest of the field to argue that epigenetic changes are reactions to underlying molecular damage.
This is somewhat threatening from my point of view. While most researchers don't agree with programmed aging, they do undertake research that is more in accordance with programmed aging than with the view of aging as damage. The strategy doesn't match to the vision of aging, for reasons that have a lot to do with the way in which clinical development is regulated. This is a huge problem, and it is why progress is slow and will continue to be slow. Most researchers believe that all that can be done to intervene in aging is to adjust the operation of metabolism into more resilient states - such as by mimicking the calorie restriction response, adjusting the epigenetics of cells in old tissues. They fully understand that the potential upside here is very limited. The programmed aging advocates think that this is great and exactly what we should be doing, and in that the presence of their faction is an additional hindrance. A battle must be fought into order to steer the research community towards effective strategies, those based on repair of damage, and this is already a tall order.
Where a therapy is newly demonstrated to be effective, the side that didn't predict it will adjust their theoretical framework to contain it. That is happening at the moment for senescent cell clearance, predicted by the damage repair advocates of the SENS rejuvenation research community. Programmed aging theorists will now argue that rising levels of senescent cells are a part of the aging program, in some way a consequence of changing epigenetics. Alternatively, both sides might agree that senescent cell accumulation has a lot to do with immune system aging, and then disagree entirely about why it is that the immune system fails with age. Based on progress to date, I'm not optimistic that this debate will be conclusively resolved any time soon, even as we enter the golden age of therapies based on repair of molecular damage, informed by the theoretical view that aging is at root caused by that damage.
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.
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 in mice. 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.