My current bird's-eye view on longevity and aging
On this page, I’ll try to summarize my current state of understanding of aging, and then retrospectively reconstruct how I have reached that state based on the papers I co-authored, aging data I analysed or took part in analysing, and, also, the general intuition I have develop from reading other studies and talking to other people working in the aging field. Of course, it’s neither extensive, self-sufficient or robust, it’s rather my subjective and intuitive framework which I usually use to test various aging hypothesis and experiments in my mind. I’ll try to leave a few links here and there where it may be helpful for a deeper understanding in the future.
Disclaimer: I’m not going to define here a lot of words which I use below, such as aging, rejuvenation, age, longevity, lifespan, healthspan, resilience, damage, stresses, diseases, biomarkers, mortality, death, longitudinal vs cross-sectional, processes vs states, dynamic vs static, entropic/stochastic vs programmatic, organism vs colony, an isolated organism or a colony/strain/line/culture, reversible vs irreversible, etc. I’ll get back to clarifying definitions in a separate post later.
By now I have somewhat independently converged to agreement with the take on aging and longevity formulated by the late Hayflick in paper one and paper two. In the best of the worlds, where all potential stressors are eliminated and the external environment is ideal, the maximum longevity would be genetically pre-defined. It’s “programmed in the genome” as the set of instructions evolution has come up with to guarantee most of us survival until the moment we need to reproduce. As a pleasant bonus, there’s a non-zero remaining safety factor, which we can exhaust to live a bit longer during our post warranty period. To add some complexity to that, of course, there is an external environment which would usually try to kill us with an infinite number of unpredictable stressors, like ever evolving viruses, for example, or microbes. We are equipped with advanced defense and repair mechanisms, which have evolved over billions of years to counteract them till the age we reproduce at, and our organism is capable of autonomously fixing enough of occuring errors to keep us alive and our reproductive system safe and functional. Everything is dynamic though: our organism and the environment that’s trying to kill us too. There’s one important difference here — we have evolved to be autonomous, with our genome inherited from our parents, and a limited volume of information and instructions it can carry, whereas the environment is unlimited in its creativity about how to stress and attack us. This fundamental imbalance is what I would call the reason causing our natural and gradual aging. It is definitely a pretty unfair game, and we are doomed to fail at some point. Unless, we stop being autonomous with the help of science and medicine, and find a way to add more tools into the defense and maintenance arsenal provided to us by evolution.
It’s an important point to digest — naively, you can count the size of your genome of 3.2 billion base pairs, and estimate it be the mere ~1.5 Gb of storage required on your computer to store it. If you think about it a bit more — isn’t it insane that a $2 USB flash drive with 2 Gb of volume is enough to encode the complete instruction set for your whole body? And given that set of instructions, you can live for almost 100 years counteracting practically infinite challenges from the environment that you are facing every second. And you never upgrade it, or replace it, and your body is never completely broken — up until the moment you die. We still have a lot to learn from biology and life about data compression and nearly perfect bioengineering.
Playing devil’s advocate, I’d say that it’s surprising that we can live for 40-50 years (sometimes longer!) without any major issues with our health, and even without any major interventions into our organisms. Have you seen a car or any complex device we can produce and engineer that would run for 50 years straight without any major breakdowns, zero downtime, even if we allow a team of engineers to continuously maintain that device? How about 100 years? Yet, we take it for granted and want to “solve aging” to live even longer, and assume that it must be easy.
But what if the body is already “perfect”, and given its current genome size and content it simply cannot live any longer. Maybe, evolution has already converged to implementing nearly all possible tricks to keep us alive as long as possible. We can try to trigger other regimes by taking medicines, or by following advice of our doctors. But what if we simply cannot extend our safety factor any further without engineering new mechanisms of maintenance, repair and defense? I don’t say that it’s impossible, and we are doomed to die by the age of 100-120. It may be a harder task, which may require more creativity from us — how do we add new protective mechanisms to our organism? We may debug our longevity and aging and find that knocking in gene X may actually extend our lifespan, but it would require us to identify that gene, and deliver it to us in some form, thus, breaking the autonomousness assumption which I’m basing my reasoning on above. In the best of the worlds, where evolution hadn’t had enough time to adapt us to live as long as possible within our environment — we might have even found a low hanging fruit, and simply reuse some mechanism that already remained dormant within us. It would have been an easy win, but then why don’t we see people in which this mechanism is accidentaly activated by a random de novo mutation? Or why don’t we see some families where extreme longevity would run from one generation to another? It implies that there may be no such dormant mechanism, and we have to actually do some research to engineer new or copy existing protective mechanisms from other species.
P.S. I never say above that life extension is impossible, and there’s a hard limit to human lifespan. Rather, my realistic optimism implies that it may turn out to be a harder task than we may naively expect. Though, I don’t see any fundamental reasons why life extension wouldn’t be practically possible at some point in the future. I hope that there are a few low hanging fruits which we may collect in the following decades.