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What do you do to live a long and happy life?
If you work on aging, you will be asked this question in every conversation. What do you take? Which drugs or interventions should I take?
Spoiler: my answer is nothing. Understanding this took me a while - but the science says: not a single thing works. No currently existing intervention can make you live to 200 or even 140 or even a hundred reliably. There is a large number of things that can make you feel better (they boil down to “behave like a kid” and don’t eat shit) but they all have the same problem:
Aging is just diminishing returns
For the same intensity of exercise, an old person makes less muscle.
For a given spoon of energy, an old person makes less functional tissue and more useless fat (or dangerous cancer).
For the same learning experience, an old person grows fewer neurons.
Wounds heal slower, making kids gets harder (to impossible), immune over or underreaction more likely. Death is eventually guaranteed.
The classical definition of aging is the exponential rise in mortality (or “damage”). But aging also implies an exponential decline in the effectiveness of interventions. This is the most important implication to understand. The concept of “Longevity Escape Velocity” is fundamentally mistaken: if the number of supplements you need to take to make it one more year grows exponentially, you will eventually need more than a year to take them all.
You cannot fast your way out of this one.
How would success look like?
Some don’t care about getting past our hard limit of 120 years, but would rather die in good health at 80. If this is your goal the current paradigm is still failing you: even the best 80-year-old athlete is frail and worse off - but more importantly: less resilient. A single injury and they are out. None of the current attempts of “increasing healthspan” will get rid of this underlying unfairness of bad luck, because they don’t address the fact that healing (even with the most advanced treatment) gets exponentially harder. And as we cannot trick the god of chance, “longevity drugs” might decrease the number of elderly without serious disease - but they fundamentally cannot reduce it to zero.
What would? Well, if 80-year-olds could drink and fuck around like 20-year-olds. Then you are guaranteed to lose them only to stupidity, not the weather. (If you really believe that there is a limit to experiences worth having you can always jump into a volcano).
If an 80-year-old were as resilient as a youngster all interventions would also be as effective. Bad news: nothing yet does this. Good news: it will be easy to tell if something does. This is how we know if something works: does it cause more or the same effect in adults as in teens?
On Silent Aging
To make this even clearer I want to introduce the term Silent Aging. Silent Aging is that thing which changes between a 20 and 30-year-old. The decrease in resilience making your hangovers worse, your wounds heal slower and your risk of becoming 40 higher. All those things that do not buckle, no matter how much exercise or fasting you do. The opposite - Unhealthy Aging - is highly malleable: obesity, smoking, high cholesterol, etc. causes more of it, so you can avoid it by being healthy.
But Silent Aging and Unhealthy Aging are additive: no lifestyle intervention lowers your age below your silent age - and even if it sometimes looks like it on epigenetic clocks, the rebound effect becomes infinitely strong eventually.
But what is it?
One way to illustrate silent aging is by looking at chronic inflammation. The older you are, the more your blood is full of signals that say “something isn’t right”. This (often called inflammaging) causes your immune system to be confused and overworked, it either gets exhausted and misses important signals from cancer cells, or it overreacts. You can increase these signals by being more stressed, fat or getting actually sick, which makes you die younger. You can also lower it by taking anti-inflammatory drugs. But surprise: those do not make you live longer. Why? Well because getting rid of the signal is not getting rid of the source - so if you stop taking the anti-inflammatory agent you get a strong rebound.
So, it’s all about senescent cells? No - senescent cells might cause inflammaging in the current model - but they can NOT be the underlying cause. Why? Because getting rid of them has the same shape! Stop taking anti-senescence drugs, and they will rebound quickly, because something is causing senescent cells to appear in the first place. Senolytics are not aging drugs (targeting silent aging), they are health drugs (targeting unhealthy aging).
Is it matrix stiffening? Mitochondrial mutations? Maybe. But only if we find that reducing stiffening or replacing mitochondria remains as easy as it is in youngsters.
There can be a cure
Even though current interventions do not target aging, this does not imply silent aging is entropy or damage. All damage can be exported (cells can already do this with 100% efficiency, otherwise the germline would age and all species extinct), but even complex organisms could do this. Have stiff tissue because of cross-links in your arm? Just toss it and grow a new one.
But this does not happen:
More Chronic Inflammation ≠More Energy Intake
This is fundamental. Old people eat less, even though they have more need for energy and building blocks to repair and regrow. The elderly refuse to cure themselves. As long as we don’t understand why, we have little chance at tackling aging.
Some theories:
- Programmed. Aging is literally degrowth. Or planned obsolescence. This is somewhat hard to explain using evolution (though I don’t think impossible), but the more relevant question is whether we can find, decode and reprogram this suicidality. I suspect this might be hard given that the program would need to be robust against defectors and therefore hard to modulate.
- Damage in the export mechanism: if you get mutations in DNA repair, you are screwed. Maybe there is a tissue-level analog (fibrosis? bioelectrical noise?) that makes it harder to turn extra energy into repair. If this were the only reason, it would lead to a high variance in observed lifespans (more childhood leukemia and some very lucky 200-year-olds), so I think it’s an incomplete explanation (but it might be necessary to address if we want everyone to make it beyond 200).
- Incorrect post-growth: Certain adaptive behavior is not shut down correctly. The thymus should shrink, because as you are older, you have seen most viruses. Keeping it active would induce autoimmunity (indeed old women get more of that, especially if you extend the bone marrow niche using hormone replacement therapy). But it obviously shouldn’t shrink to zero, which it seems to do. This is also true in the brain: pruning synapsis (which kills neurons) is a good forcing function to compress your world models. But you only grow new ones if you get surprised, which just doesn’t happen as often later on. If pruning is not “shut off” at the right time we just lose our brains.
- Repair is risky: we are warm-blooded animals made of 30 trillion cells and 40 trillion microbes. Repair requires remodeling, which requires loosening of constraints, which creates the perfect microenvironment for invasion (infection) or defection (cancer). We cannot afford to regenerate our lost limbs, we have to do scarring (rapid overtightening of constraints). Adding more energy would not help, on the contrary. If you had to be worried about adding heat to metal, all swords would be brittle.
- Parasites: Your body would love to spend energy on repair, but it is full of pure consumers: parasitic fat cells, unnecessary immune cells, corrupt stem cells, the wrong microbiome.
This is one of the better explanations for the decline in cognitive function between ages 20 and 40, but in the elderly, the rate of loss in brain mass rises, so pruning is at least not linear and probably modulated by other stressors.
When you turn 20 your energy needs should drop - there is no more growth, but the amount needed for homeostasis remains constant. But this does not happen; instead, you get fat. You will slowly eat less to avoid obesity, while your need actually increases (repair). When you get so broken that you really have to eat more, you already have so many non-functional cells that gobble up excess energy that nothing would reach the crucial tissues.
One could make up more theories, the point remains. If we understand which interventions change how the system converts energy into healing, rather than how we can heal or add energy, we have a chance at finding a cure for aging. One that does not become less effective the older you get.
Epilogue: Are there hints?
As said, I currently don’t really do anything for aging. I do some things for health, or rather vitality (mostly just aping around, [high amount of spontaneous movement], curiosity and wonder at everything, hanging upside down, sleeping between 0 and 14 hours at random times, forgetting to eat [and then eating Haribo], you know: child things).
But there are some things I am excited about:
- Replacement: If you can safely put in a new thing rather than trying to repair the old one, you only get diminishing returns at the border. Fecal transplants for example are amazing: they will always work, and if they don’t it’s because the gut lining is old. This will be doable with more and more organs, and even brain-specific cells like microglia. It won’t work with the brain tissue itself, but that’s why we need to study how much the brain actually silently ages.
- Anti-fibrosis: I don’t think extracellular matrix stiffening (micro-scarring) is because of “irreversible” cross-links, it’s more a change in the dynamics of ECM remodeling (the tissues that do not get remodeled are also the most static, and therefore easiest to replace [eye lens, ligaments]). This makes me excited about all forms of physical anti-stiffeners, like shockwave therapy (not yet tried, but will soon). Those really could not hit diminishing returns, at least in principle.
- Turning the immune system on and off: one of the reasons we don’t want a hyperactive immune system is because of autoimmunity. But you only get self-attacking memory cells under narrow conditions (very few people get type 1 diabetes [memory for beta-cells] in older ages). If you could just wipe these memory cells (which seems possible with CAR-T or some future method), we can not only cure those diseases, but we can safely ramp up the immune system. I suspect there might be conditions under which silent aging can be completely repressed by a strong enough one (assuming that it just overwhelmed and hasn’t gotten to “inbox zero”).
- Engineered regeneration: Michael Levin (our lord and savior) will eventually get humans to just regrow limbs. I suspect this is closer than we think. This does not just allow complete (no diminishing return) regeneration of limbs (and therefore mobility) it also allows cooler moves (like nuking one of your kidneys, letting a fresh one grow there instead, and then regrowing the other one). This avoids some of the hard problems of surgical replacement (just hasn’t been done), while keeping the benefit of being “molecular biology agnostic”.