Note: I view this type of research as a good rationale for why I move beyond just “Kale and Cardio”, and into rapamycin and SGLT2 inhibitors, and potentially the SS-31 peptide, etc.
A groundbreaking theoretical study from the Alon Lab at the Weizmann Institute has mathematically formalized a frustrating truth for the longevity community: “optimization” is not “extension.” By analyzing extensive human demographic data through the lens of a “Saturating-Removal” (SR) mechanistic model, the authors propose that human aging is governed by two distinct classes of parameters.
The first class—Threshold (Xc) and Noise (ϵ)—determines the shape of the survival curve. The study demonstrates that lifestyle interventions (diet, sleep, exercise) and historical medical advances primarily act on these parameters. They “rectangularize” the curve, pushing more people toward the median lifespan and reducing early death, but they hit a hard wall. The model predicts that even perfect lifestyle optimization can extend maximal lifespan by at most ~1 year.
The second class—Damage Production (η) and Removal (β)—sets the absolute speed limit of aging. The authors show that these rates are evolutionarily conserved and incredibly rigid in humans. Variations in these rates of just a few percent would result in unrealistically long lifespans (e.g., 160+ years), which we simply do not see. The study validates this by analyzing Progeria (Hutchinson-Gilford syndrome), showing that accelerated aging does result from catastrophic changes to these specific production/removal parameters.
The Big Idea: We have maxed out what “maintenance” (lifestyle) can do. Breaking the 120-year glass ceiling requires “engineering”—specifically, interventions that lower the rate of damage production (e.g., slowing epigenetic noise) or radically upgrade clearance (e.g., potent senolytics), mechanisms that current “Blue Zone” habits fail to touch.
Context: Weizmann Institute of Science, Israel. Published in bioRxiv (2025). Impact Evaluation:bioRxiv is a repository for rapid dissemination of research prior to peer review. While it lacks a formal Impact Factor, top-tier papers in this field often appear here first. Treat this as High-Visibility / Preliminary Consensus rather than peer-reviewed doctrine.
Novelty
This paper resolves the “Strehler-Mildvan correlation” paradox, showing that human heterogeneity is strictly confined to noise/threshold parameters. It provides a mathematical proof for why no amount of broccoli or jogging will get you to 150. It explicitly decouples “healthspan” mechanisms (robustness against noise) from “lifespan” mechanisms (damage kinetics).
Critical Limitations
Zero Wet-Lab Validation: This is a pure modeling paper. No biological compounds were tested in vivo to confirm that altering η or β is actually possible in humans without lethal side effects.
One can reasonably hope to defeat cardiovascular disease, organ failure and sarcopenia with the right interventions. That leaves you with infections, cancer, AD, accidents and biological limits like telomere length, destruction of the ecm etc.
This is only interesting if you think the underlying model (“SR”) makes sense. Scanning the references, I’m not convinced. Does anyone care to steelman this?
For women, there is only 1 documented to have lived beyond 120y.
Jeanne Calment died at 122y-164days, but she’s possibly a case of fraud.
There are none a 121y, none at 120y… next women made it to 119y
For men, none at 120y and above, none at 119y, none at 118y, none at 117y
Jiroemon Kimura died at 116y-54days
The 120 year maximum is unlikely to be explained by a DNA program or the hayflick limit.
Note that billions of people each with unique genomes have lived in documented history, yet none of them lived past 120. That means that genes don’t explain the limit, at least not within natural variation in genes. Other constrains are important here, such as extracellular matrix damages and non-cellular damages that slowly accumulate with age and limit how long cells in the body can live.
The limit looks less like a hard genetic limit clock to me (if it were such a clock we would likely see outliers with incredibly lucky genetic makeup live well past 120) and more like a limit imposed by slow accumulation of damages that are not determined so much by genes.
I like to be more specific as the ECM is comprised of many things, some may be “easily” fixed but the elastin problem is the most complex aspect of the ECM that currently has no proposed solution that I can find.
I don’t think any of the ECM problems can be easily fixed (none of the major ECM damages or problems have good solutions on the horizon) but I agree with you that elastin is an example of one that is relatively complex and extra hard to fix. It’s one that deserves serious attention IMO.
It’s more about the design, where genes must be seen in the context of not individual genes acting alone or only in concert with a limited number of genes, but design as in the totality of growth and development. The current genetic makeup cannot get around stochastic damage and repair limitations - it was not designed to do so. There was not evolutionary pressure for a different design that would favor longevity beyond what the current limitations for humans are. But think of the bowhead whale or greenland shark or whatnot living 200-400 year lifespans - it’s not an issue of a few genes that are changed and would allow for 100%-300% lifespan extension like it is in the elegans or simpler organisms. By the time you get to mammals, there are so many moving parts that you need to pretty much overhaul the whole genetic makeup and 90%+ of the whole genome. Mammals have developed solutions that are often limited timewise, because there was no pressure to extend - so our hormonal systems or other systems evolved to last only as long as they had to. Imagine a bridge that has pillars that are limited to bear only X amount of weight. There will be individual differences where the same “thin” pillar might take X+/-20% of the weight depending on some additional conditions. But those pillars will not take X+300% weight. You need different pillars.
And so, simple genetic engineering - as in altering a limited number of genes - might give us that +20%, but then you are going to run into the limitations of the design itself. To get to +300%, you are going to have to change the design, which means changing almost the whole genome. And that, dear friends, is a serious engineering challenge - I can picture running some kind of computer simulations where you put the genes under longevity selection pressure and see what you come up with in order to get to +300%, but then you will need to implement it. Nowhere near our lifetimes. In fact, within our lifespans (i.e. the next 50-70 years depending on how young you are, dear reader!) I would not anticipate extending the 120 year limit at all - I’d at best hope for allowing you to fulfill whatever biological potential your parents endowed you with, fixing weak links etc.
Anything else is a pipedream at present. Maybe in another 100 years, assuming rapid scientific progress, adequate funds and societal pressure. I’m not holding my breath. Let’s see what the next few years brings us - so far we’re stuck with whatever CR gave us already in the 1930’s and rapa in the 60’s-2000’s. We still have not come up with anything better in mammals in close to 100 years. Pathetic. YMMV.
