I generally agree with aging = accumulated damage. But not only by oxygen. Whales store more oxygen in their tissues then humans, but they leave up to 200 years and raise the Peto paradox. So the answer should lay in damage prevention mechanisms. Which we don't know. So what we know, that needs to be done? Because 1000 mutations is not a practical solution.
Btw, the article below states that oxidative damage is a minor contributor to mutation burden. With the majority of mutations coming just from random deamination and replication errors.
https://www.nature.com/articles/s41586-021-03822-7
Yes, I agree that oxygen is not the most important (probably). That's an abstraction representing that we can't ever get rid of damage because it is as ubiquitous as oxygen is.
With coordinated efforts, 1000 mutations is a practical solution.
There are multiple alternatives.
Growing organs outside of the body with those 1000 mutations present.
It is an engineering problem. Replacing cells and making cells rejuvenate the tissues is also an engineering problem.
But humans did not evolve that.
Why? Because we are too complicated.
Most biological procesess are highly conserved in evolution. Identical biochemical pathways in all organisms. I can kill with Cyanide yeast cell, a worm/fly, a dog and a dog's owner. Potentially, Cyanide can killa life from Mars. Al this horror is possible because Cyanide inhibit evolutionary conseved mitochondrial complex IV.
And this is very common. Most biochemical pathways can be tracked down to bacteria. Many developmental genes and mechanisms are similar in fly and mammal. many physiological features (kidney function) comparable in fly and mammal.
Most molecular mechanisms responsible for corrections are highly conseved. DNA repair, RNA splicing. Proteosomes.
We are not that complex. This is why complexety has nothing to do with aging.
A whale does not live long because every one of the millions of mutations separating it from a human is necessary for longevity. Most of those differences are related to body shape, development, ecology, metabolism, and many traits that may be largely irrelevant to lifespan extension.
The long-lived species contain a smaller number of especially valuable architectural solutions: better cancer suppression, more robust proteostasis, improved DNA repair, slower damage production, or more effective tissue maintenance. Some of these solutions may be partially reproducible in humans without turning a human into a whale.
This is not merely hypothetical anymore: bowhead-whale CIRBP enhances both non-homologous end joining and homologous recombination repair in human cells, while overexpression of human and bowhead-whale CIRBP extends lifespan in Drosophila.
Yep, it's a good read. Also this article doesn't show that wCIRBP is functionally different from hCIRBP, it just has a naturally higher expressjon. It would be interesting to see hCIRBP overexpression in vivo. Until then we have to rely on cold showers:)
Basic metabolic rate and body mass are not determining longevity.
It was described long ago by Pedro.
https://pubmed.ncbi.nlm.nih.gov/17339640/
Actually, being big and living longer is harder (no source). But those animals live longer because they rarely reproduce, and living longer is a way to compensate. (Pedro).
If you compare a whale to turtle, a whale has a much much higher metabolic rate than a turtle because it is warm blooded. Yet, whales live longer than turtles. Basic metabolic rate does not limit lifespan.
Oxygen and reactive oxygen species (ROS) do damage proteins, lipids, and DNA. However, the strong version of the free-radical theory of aging has not held up well experimentally. In mice, genetic overexpression of major antioxidant enzymes generally does not extend lifespan. For example, overexpression of CuZnSOD, MnSOD, catalase, or combinations of these enzymes failed to produce a consistent lifespan extension in mice. ROS are also not merely harmful by-products: they play important signaling roles, and in some contexts an increase in ROS can even be associated with longer lifespan.
Useful references:
Viña J. et al. The Free Radical Theory of Aging Revisited: The Cell Signaling Disruption Theory of Aging. Antioxidants & Redox Signaling, 2013.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3749699/
Pérez V.I. et al. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell, 2009.
https://doi.org/10.1111/j.1474-9726.2008.00449.x
Several thousand mutations can radically extend lifespan.
Since the biological body is dragging us into the grave, let’s maximally reduce the burden of flesh by moving to an artificial body with a brain transplanted into it. Then we would only need hundreds, not thousands, of mutations and significantly fewer therapies of other types — compared to maintaining our constantly aging body as a whole.
Stable isotope analysis in archaeology and forensic science: isotopic signatures in bone can typically be traced for no more than 7 years after consumption. Even ribs, for example, are substantially remodeled over time and molecular components will be replaced within 5-7 years. This raises an important conceptual question: how can any molecular damage persist and accumulate in biological systems against such a highly dynamic background of continuous molecular turnover and replacement?
"...8-week chase period and dilution by oocyte growth, we detected many 13C6-Lys-positive proteins (768 out of 7,263 proteins), "
https://www.nature.com/articles/s41556-024-01442-7
Just 10% proteins remained labeled after ~2 months of "chase". The paper on ovaries, last time point was 6 moths. Rule, function: every 2 months, 90% replacement of the proteome. How damages can persist?
If you look at our body as an information system - the errors do not necessarily persist in the same exact molecules, but they still get passed on. Newly synthesized DNA passes mutations to daugher cells. Senescent cells pass damage via SASP and increased ROS to their neighbours. Misfolded proteins disrupt homeostasis and cause more damage even if they are being degraded. When the rate of damage becomes higher than the rate of repair the process becomes exponential and irreversable.
0) Any damage is stochastic in nature. Biology is highly conservative. Biological processes and pathways in worms and mammals are remarkably similar. Why, then, should a set of such similar pathways be affected differently by stochastic processes?
1) Please define protein "damage".
2) ROS, oxydative damage hypothesis has been disregaded. Anti-oxidants or over-expression of corresponding enzymes actually decreased the lifespans of many lab animals.
3) "...the errors do not necessarily persist in the same exact molecules, but they still get passed on." Exept prions, there are no evidances on information pass from one protein to another.
Elastin and many other proteins in the matrix are never replaced. Never.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11659964/
You attached oocytes, a cell type specifically designed to be long-lastin and contain fresh proteins to improve the fitness of the progeny. That is not valid for somatic tissues.
This is directionally plausible, but it does not yet answer the question.
First, the paper does not show a universal rule that 90% of the proteome is replaced every two months. It detected residual label in 768 proteins after an eight-week chase, with very different retained fractions. In the whole ovary, more than 10% of proteins had estimated half-lives above 100 days, and some persisted for almost the entire mouse lifespan.
Second, rapid turnover does rule out a naive model in which ordinary damaged proteins simply sit in place and accumulate for decades. To explain persistent damage, one has to identify the substrate that stores it: genuinely long-lived proteins or extracellular matrix, DNA or mtDNA mutations, long-lived cells, stem-cell clones, persistent epigenetic states, or a self-maintaining failure of quality-control systems.
These are distinct mechanisms. SASP, ROS and misfolded proteins may contribute in specific cases, but they do not automatically imply exponential or irreversible propagation of damage. That requires evidence for a concrete feedback loop.
In my worldview, we understand the cause of aging. The deep cause is physical.
We live in an oxygen-rich atmosphere. Oxygen oxidizes molecules. Molecules break. Proteins misfold. DNA is damaged. Cells drift away from their original state. A living organism is not a stable object. It is an unstable, self-repairing system that survives only because it constantly renews itself.
This is why I really like the latest papers of Ben Shenhar and Peter Fedichev: aging can be viewed as the balance between damage accumulation and damage recovery. At some point, damage recovery cannot keep up. That limit is what shapes maximum lifespan.
So in that sense, the root cause cannot simply be “removed.” The cause is not one bacterium, one pathway, one toxin, or one evolutionary mistake. The cause is oxygen in the atmosphere, thermodynamics, and the fact that we are made of unstable molecules. Of course, one can freeze oneself, but that is not solving the problem.
This is the important distinction: the underlying cause of damage accumulation is external to life. It is not a property of life itself. In fact, a living system is alive precisely because it is fighting this external pressure. Life is not aging because it wants to age. Life is aging because it is constantly resisting decay, and eventually failing.
But why then do living systems fail to resist degradation forever?
This is where plaques may enter the picture. They definitely shape maximum lifespan. They create pressure. They may prevent the evolution of cleaner, longer-lived, better-maintained organisms. But they are still secondary.
You can imagine an organism with no plaques at all, and it would still age. You can remove every obvious external disease factor, and oxygen would still be there. Molecular instability would still be there. Damage would still accumulate.
Hydra avoids aging by making every cell replaceable. In principle, if humans could replace every cell in the body with a fresh version, we would not age at all.
So why does that not happen?
The answer is probably not that nature “could not” do it in some abstract sense. We can imagine breeding species (humans) for millions of years toward longer and longer lifespans. Maybe, eventually, a mechanism could evolve that replaces every cell, every structure, every damaged component, while preserving the organism’s identity and function.
But humans did not evolve that.
Why? Because we are too complicated. Because replacing every cell in a tiny simple organism is one thing, and replacing every cell in a brain, immune system, vasculature, endocrine system, reproductive system, and memory-bearing organism is another. Because evolution optimizes under constraints. Because selection weakens after reproduction. Because pathogen pressure and many other forces may have made such a strategy too costly or too unlikely to evolve.
This is where the plaque hypothesis might matter. It may partially explain why some long-term maintenance mechanisms never evolved in vertebrates.
But it does not solve the central problem.
Even if we removed all plaques completely today, we would still not suddenly have a body-wide mechanism for perfect renewal. We would still not have a natural way to replace every old cell, every damaged structure, every drifted molecular state with a fresh one. We would still need to fight oxygen, entropy, instability, and accumulated damage.
Let me just drop it here:
Several thousand mutations can radically extend lifespan.
Several million mutations will make a human a whale.
References:
https://www.biorxiv.org/content/10.64898/2025.12.22.695887v1
https://www.biorxiv.org/content/10.1101/2025.08.25.671954v3