My Year of Aging Dangerously: How old is too old to rejuvenate?

Bloomberg article, July 11, 2025: Journalist’s personal account of taking on the aging process at age 66.

" I always believed in rejuvenation. So, I shuddered at a recent Stanford University medical paper about the human timetable for aging. It concluded that people grow older not gradually but in two clumps, approximately when we turn 44 and 60 years old. The researchers reached this conclusion after tracking the blood samples of 108 individuals and compiling profiles of their “-omics” — shorthand for biological data based on microbiomes, proteomes, lipidomes, transcriptomes, etc. That would be the microbes at work in our guts and organs, as well as the proteins and lipids at the cellular level, plus the genes transcribed into RNA molecules."

https://archive.is/psyaW

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Unfortunately (becoming my favorite word), as far as I can tell, there is nothing that actually extends lifespan. The so-called lifespan increases can be explained by eliminating those things that kill us: cancer, CVD, etc. What we are really doing is increasing healthspan, which makes it look on charts that we have increased lifespan.

“Consistent with the statements above, these analyses revealed links to cancer inhibition in >80% of these interventions (Table [1]i.e., there is no need to assume that general aging-associated physiological decline was slowed to explain the pro-longevity effects).”

So the fact that I have lived past my “use by date” is because I have not contracted any fatal illnesses as yet.

https://www.nature.com/articles/s41380-022-01680-x?fromPaywallRec=true

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Not only does the best evidence support your view IMO, those focused on lifespan might do better for themselves if they internalized it. In almost all cases, something very specific will kill each of us. Let’s do our best to avoid it. We know we’re going to lose in the long run but we can score points along the way.

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Yes. It’s the bog standard “weakest link” paradigm. Whatever is your weakest point, is what will kill you. Heart. Lung. Brain. Liver cancer. Some obscure system you never paid attention to or perhaps were even aware of. And the closer you come to the age when that weakest link will fail, the greater your risk of death. Age progression is the process of getting closer to death.

Which is why there are two approaches to this problem. One is “whack a mole”, fix your weakest link, then the next weakest one and so on always one step away from failure. Take a statin for the CV system, BP meds etc. The second one is to slow the approach to the failure point, slow the aging process itself. You will still die of your weakest link, but you’ll just get to that link failure later in time. The second approach is the one Matt Kaeberlein specifically advocates. In animals CR is the only intervention which slows down the rate of aging itself. Can it be implemented in humans? Perhaps.

Rapamycin is an interesting case. Does it prolong life in animals by slowing down the rate of aging itself, like CR does through a different mechanism, or does it work by globally fixing a raft of different weaknesses simultaneously, a collection of weak links most animals have inherent in their design?

In other words, does it work like CR or like an uber-statin?

Either way, short of changing the design of our organisms with something like genetic engineering, all we are doing at present is fiddling at the margins.

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I still don’t know what this means to the average Joe.
Going on a diet is a calorie restriction. And, yes, it is possible that dieting extends lifespan.

But what does CR mean long term?

If I maintain a BMI lower than the norm, am I on CR?

We all have our personal drums to beat. One of mine is that maintaining a BMI in the lower half of the “normal” BMI range for most people can cure a multitude of ills, such as plaque accumulation.

“A healthy BMI range for adults is generally considered to be 18.5 to 24.9. This range indicates a healthy weight in relation to height for most adults.”

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CR is just maintaining a deficit of what you normally eat. So if you normally eat 2000 kcal a day, a 10% deficit CR is 1800 kcal. That’s calorie restriction, you’ve restricted calories by 200.

I guess metabolic rate barely changes with weight (which is why people keep gaining weight even on a small surplus).

But weight decreasing with age might be cancer cataxia.

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No. Maintaining low BMI is not CR. CR is specifically maintaining low calories, regardless of BMI. The vast majority of time, being in a calorie deficit will result in a low BMI. But there’s a wrinkle. The animals that lose less weight on CR live longer. So if you take two same size age etc. animals, and both are on a calorie deficit of the same size (say, 30%), the animal that loses less weight on that deficit will live longer. Meanwhile BMI by itself is not indicative of being calorie restricted. You can have huge intake of calories, but huge expenditure through, say, exercise and maintain low calories - athletes do that all the time. They are not restricting calories therefore by definition they are not calorie restricted, not on CR, even though their BMI might be pretty low, like a marathon runner or swimmer. And multiple experiments have shown that exercise, unlike CR, does not extend max lifespan, although it does lower premature mortality. You cannot exercise your way to a longer lifespan, though you can to some degree exercise your way to a longer healthspan.

If you want to be on CR, you must be on CR, i.e. you must restrict calories, not simply expend more. But again, as so often, there are exceptions. Holloszy et. al showed that if you expend the calories specifically by generating warmth, you can take in more calories, yet achieve physiological results that mimic CR - so the elusive CR without restricting calories (much) - at least in rats (the rats with cold feet experiments - having rats live in cages with cold water, so they are always soaked in cold water). This is one instance where expenditure of energy - unlike exercise - does impact lifespan without equivalent restriction of calories (but only to a degree, overfeeding is still detrimental - simply you are allowed to eat a bit more). Does it work in humans? Perhaps. That was the whole shift to CE (cold exposure) paradigm of slowing aging that preoccupied the CR Society in the last few years before the site went offline. Many members shifted from CR to CE as they felt the science was more solid in CE and for some more doable than CR. So, to achieve the slowing of aging, you have basically two options: be hungry, or be cold. Now, there is the pursuit of slowing down aging without hunger or cold, by drugs, and that’s where rapalogs enter - but it’s all rather complicated.

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I think Im on CR. I’m usually hungry and often cold. Being on CR is easy especially for a vegetarian. It could be an explanation why a reduced rapamycin dose works so well for me. Whatever rapamycin doesn’t cover CR does. They may work synergistically. My BMI is 19.5. I’m not sure if maintaining lower weight will continue benefitting me after 70.

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It depends on what you eat.

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Why not? I’m 77, weigh 140, and can’t imagine putting on extra pounds. I’m not a strict vegetarian, but I have restrictions, as you probably do, on sodium, potassium, phosphorous, and protein.

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Thanks for linking that article. I think they raise an interesting point, but their analysis is far too simplistic do anything more than that.

As they allude to, 70-90% of lab mice die of cancer, which means that basically any drug that increases median lifespan will have to suppress cancer. Suppressing cancer and slowing aging aren’t mutually exclusive. On the contrary, cancer is a disease of aging, so any drug that fundamentally slows aging should also generally suppress cancer. Of course it should also suppress other aging phenotypes as well, but that evidence is also piling up for mice interventions!

Their whole “analysis” is summed up in this paragraph:

Table 1 summarizes the different types of anti-cancer evidence for each of the putative aging regulators considered here. Interestingly, for 100% of these interventions, an anti-cancer role has been shown in “induced” mouse cancer models. For 93% of these interventions, an anti-cancer effect has also been found in cancer cell lines. These observations strongly support the notion of direct and aging-independent anti-cancer effects. As a consequence, given that aging-independent anti-cancer effects are documented for most of the putative aging regulators (Table 1), a straightforward, yet underappreciated mechanistic explanation for much of the pro-longevity effects afforded by these interventions in mice is that they are not induced by “slowing aging” but rather by the direct inhibition of lethal neoplastic disease via aging-independent mechanisms.

As they provide no evidence that these processes are mutually exclusive and without some deeper level of analysis, the entire conclusion rests upon their defining that efficacy in induced cancer models implies anging independent mechanisms.

In fact, I would argue the opposite: if a drug genuinely slows aging, it should also reduce mortality in induced cancer models. Cancer is fundamentally an evolutionary process driven by rapid cell division and accumulated damage. Slowing aging processes—such as reducing genomic and epigenetic instability or improving DNA repair—could plausibly slow the “evolutionary clock” of cancer development even in induced models.

Furthermore, cell division is extremely damaging in and of itself. Replication fork collapses lead to double-strand breaks which generate indels and chromosomal rearrangements, as well as epigenetic rearrangements. Drugs which slow cell division might slow the rate at which these types of damages occur—is it any surprise that rapamycin extends lifespan in every species tested and also slows the rate of cell division? Perhaps cytostatic drugs should not be assumed to be mutually exclusive from anti-aging drugs.

There is a mechanistic caveat that cell division can also act to dilute molecular damage (and another that drugs which stimulate cell division often promote cell survival). I think in certain tissues like skin, which perhaps due to constant UV exposure and the need for increased (epi)genomic stability and DNA repair, this dilution might outweigh damage caused by division (the evidence for this being drugs like tretinoin improving skin quality even over decades of use), whereas in other tissues it might be more beneficial to slow tissue turnover to a near halt.

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As a disposition @CronosTempi, I take your point and agree with much of it. However, juxtaposing, systematically fortifying or reducing weak points with slowing down the process of aging itself might draw on a distinction with less of a difference than we might suppose. The resolution of that position rests on considerable empirical evidence yet to be acquired in this nascent field. Some specialists reject the notion that “the aging process” is anything more than a handy catch-all term that subsumes many individual systems and processes we group into the notion of “aging,.” Cancer being a familiar example. On this view, slowing aging just is systematically fortifying weak points.

Speaking of changing the design of humans, the CRISPR-based gene-editing to target the PCSK9 gene is approaching that category but, again, some would argue that is it targeting a weak point cf. slowing down the aging process.

Interesting ideas to contemplate as we learn more.

I think there’s a corollary to this which is that if molecule A can prolong the healthy function of a given vital organ (let’s call it organ A and assume it is not often an initial failure point), it will exhibit synergy with molecules XYZ that prolong the functions of vital organs XYZ (assuming these organs usually fail first). Essentially molecules XYZ unmask organ A as your new weakest link, so that now molecule A can produce life extension in the presence of molecules XYZ.

This is why I don’t think we should summarily dismiss drugs solely because they failed in the ITP. We should have reduced confidence in their efficacy as longevity drugs in isolation, but we should still be open-minded about their potential efficacy in combinations.

Of course for some small percentage of the population, organ A will naturally be their weakest link and molecule A will prolong their life by itself. Due to the small percentage size, life extension will be more difficult to detect in this case.

This is what I would call an “interaction-free” synergy, which rests on something akin to a biological superposition principle. Of course, when these molecules interact (for example by interfering with each other’s metabolism, altering one another’s target recognition, or altering the way organs interact with one another) there might be still be synergy, but it becomes of a more complicated nature.

Either way, short of changing the design of our organisms with something like genetic engineering, all we are doing at present is fiddling at the margins.

Totally agree. Small molecules just don’t have the “degrees of freedom” needed to substantially change our physiology, which is what truly striking lifespan increases would require. And even in the cases where we can modulate the activity of a membrane receptor or intracellular enzyme, we’re generally limited to reducing its activity rather than increasing it (it’s way easier to turn off an enzyme or receptor than to activate it, which is why inhibitors/antagonists/NAMs have dominated drug discovery compared to activators/PAMs)

That was the whole shift to CE (cold exposure) paradigm of slowing aging that preoccupied the CR Society in the last few years before the site went offline. Many members shifted from CR to CE as they felt the science was more solid in CE and for some more doable than CR. So, to achieve the slowing of aging, you have basically two options: be hungry, or be cold. Now, there is the pursuit of slowing down aging without hunger or cold, by drugs, and that’s where rapalogs enter - but it’s all rather complicated.

I think it’s quite likely from the data that reducing temperature by reducing heat generation/metabolic rate in some way is an effective longevity intervention. CE is not the same thing though—it’s essentially reducing temperature by pulling heat out of the body (which a priori might affect heat generation in any which way), and I haven’t seen much data that it’s an effective longevity intervention.

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Yes, there is that view. That way of conceiving the process of aging is not supported very well. Evidence against it is abundant. Progeria - not exactly “wear and tear” or multiple systems somehow unluckily failing simultaneously and at roughly the same speed. Looking at that phenotype, it has the classic hallmarks of aging, except in an accelerated timeframe. You can see it in all the tissues. At the other end, you can see certain sea creatures, including some crustaceans that seem not age, and examining the tissues you don’t detect hallmarks of aging. In some there is process in juxtaposition - growth. They keep growing. This way they avoid the usual path of growth-maturity-decline-death, because they’re permanently stuck in the first phase, growth, thus skipping the aging process. They do die eventually, victims of predation, but also eventual failure of moulding as they become too big for the moulding process to complete in time - but they die without their tissues showing hallmarks of aging.

The genetic engineering to prevent cancer or heart disease is interesting. It sure could extend average lifespan, but it’s hard to argue that it’s slowing aging. It’s curing a disease, and yes, it would prolong the life of those individuals who would otherwise die of cancer or CVD prematurely. On a population level you gain a handful of years. In some species it might be a goodly amount - most lab mice die of cancer. Preventing cancer gets them a few months, decent percentage of lifespan extension. But that’s not slowing aging. Look at the sister species that escaped the usual size-lifespan rule, the naked molerat. That animal can live in excess of thirty years. No amount of disease curing or prevention is going to get a mouse within a galaxy of that kind of lifespan.

Anyhow, it’s pretty clear that we need to do similar genetic engineering for ourselves that nature has evolved for the naked molerat - ten times our current max lifespan, some 1000-1200 years, I’ll take it! Sadly not in our lifetimes.

You are being pessimistic. I am of a generation that had no TVs, computers, and only one available antibiotic (penicillin) when I was born. I have witnessed the exponential growth of all sciences. Now with the advent of AI (hoping it doesn’t kill your generation), things will speed up even faster. My guess is that anyone under ~60 years old can look forward to being at least 100 years old.

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Absolutely. Which is why I’m a huge advocate for polypharmacy (carefully curated), to the outraged protestations of the lifestyle-optimising-drug-avoiding naturalist purists who seem content to live only as long as nature happened to randomly evolve for our species. Look at metformin by itself which does nothing much for lifespan in the ITP, but synergises with rapa to positive effect. I think there are likely better drugs than metformin which address the same pathways, but it illustrates the principle.

Re: CE, you are underestimating the scientific evidence here :smile:. There is abundant evidence that cold temperatures extend the lifespans of animals in those environments. I don’t want to get into it here, because it’s a whole other universe of data… that’s one of the biggest losses in the demise of the CR Society website - there was a ton of research gathered on CE in one place. A unique resource.

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You are being overly optimistic😂. When the first airplane flew, and then the atomic energy was harnessed people thought the Jetsons were just around the corner. No dice.

I’m almost your age and have a very different recollection of technological and scientific progress. It progresses by cycles. Big breakthrough, but then a period of consolidation and stagnation until the next leap. And every time there was a leap, people thought that it was a steady rocket ride upward. But the breakthroughs showed their limitations very quickly. I have also been through these cycles. I have studied history. Yes, on a biological species timeline the technological explosion is extraordinarily rapid. But on an individual human lifespan scale, it’s rather slow and disappointing (because much better could be done if we put our resources to work consistently and intelligently).

Atomic power - we thought fusion was around the corner. Seventy years later, we still don’t have a working fusion reactor. Computers in the 50’s - cybernetics was an actual field with dreams of autonomous robots, still mostly a dream decades later. And AI is very old, starting with Minsky and his optimistic work in the 50’s. Still no AGI on the horizon, despite regular outbursts of optimism - do you remember when we thought Expert Systems of the 80’s meant AGI around the corner? All it resulted in is automated voicemail as the biggest impact. Today’s LLM based AI models are just souped up ES, laughably far from AGI - for true AGI you need a paradigm shift in approach, a real series of huge breakthroughs (which will surely come, just not soon).

When the DNA structure was described in the 60’s we thought all disease would be cured soon. LOL. Then came the biotech explosion of the 80’s and a cure for everything hope. LOL. Stem cell research and hopes of a glorious future. LOL. Then the human genome was sequenced, and again nirvana. That was quarter of a century ago. LOL. Now we have had CRISPR that gave us all a collective orgasm. It’s been a few years and I feel an unmistakable LOL coming on.

I don’t think there are many certainties in predicting the future. But we all assess the situation and bet on what’s most likely. I place my bets very confidently that the current AI will be another case of a big LOL down the road, and same with current longevity science efforts - a big LOL. As Matt Kaeberlein said: it’s a scandal that we’ve had rapamycin around for decades 30-40 years or more and we still don’t have a drug that does better in provably prolonging life even in manalian animal models. Thirty years of running in place and nothing better is an indictment of the whole process of doing life extension science. And a very pessimistic forecast of what’s to come and at what pace. That is the cold hard truth of reality. I’d love nothing more, OBVIOUSLY (!), than to be proven wrong and a gloriously rapid progress to suddenly and miraculously descend upon the field of longevity science, but my rational faculties tell me the odds are slim to none.

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Re: CE, you are underestimating the scientific evidence here :smile:. There is abundant evidence that cold temperatures extend the lifespans of animals in those environments. I don’t want to get into it here, because it’s a whole other universe of data… that’s one of the biggest losses in the demise of the CR Society website - there was a ton of research gathered on CE in one place. A unique resource.

Probably, I know that hyperthermia greatly increases the neurotoxicity of MDMA, but I haven’t looked much into the connection with longevity. :laughing: If you have any papers on how cold environments affect longevity that you think are important please share. Obviously reaction rates generally increase with temperature, so I certainly find it plausible that extrinsically lowered body temp can lower “effective” temperature.

CRISPR is a great technology but still kind of experimental right now. 20-30 years from now on it will be used for regular treatments. Still no silver bullet for defeating aging.

You raise good points --all of them – @CronosTempi. The differences in our views spring mostly from where we find ourselves on the spectrum of this artificial dichotomy.

Viewpoint 1: Geroscience Hypothesis — Aging as a Primary, Targetable Driver of Disease
This is arguably the dominant paradigm in modern aging research and has substantial theoretical and empirical support. Its core tenet posits that there is a set of core biological processes that drive aging itself. These processes are the primary risk factor for nearly all major chronic diseases, including cancer, neurodegeneration, and, of course, atherosclerotic cardiovascular disease (ASCVD). By targeting these core processes, we can simultaneously delay or prevent a wide spectrum of age-related diseases and extend healthspan.

The currently recognized hallmarks include:

  • Genomic instability
  • Telomere attrition
  • Epigenetic alterations
  • Loss of proteostasis
  • Disabled macroautophagy
  • Deregulated nutrient-sensing
  • Mitochondrial dysfunction
  • Cellular senescence
  • Stem cell exhaustion
  • Altered intercellular communication
  • Chronic inflammation (Inflammaging)
  • Dysbiosis

Taking Apo(b) as a discussion point. Apo(b)-containing lipoproteins are not just a risk factor for a plumbing problem in the arteries. They are a direct driver of at least two hallmarks: deregulated nutrient-sensing (lipids are key signaling molecules) and chronic inflammation. The deposition of LDL particles in the arterial wall incites an inflammatory response that is a classic example of localized inflammaging, which can then become systemic. Therefore, lowering Apo(b) is not merely disease prevention; it is a geroprotective intervention that targets a core hallmark.

Viewpoint 2: Network Failure Hypothesis — Aging as an Emergent Property of Decline Within and Between Interconnected Systems

This view does not contradict the Geroscience Hypothesis but rather reframes it. It is less about a single “program” of aging and more about the emergent property of a complex, interconnected system losing its resilience. The core tenant here is seeing the organism as a robust network of interacting physiological systems optimized for function in early life. Aging is the progressive and accelerating failure of this network. The “hallmarks” (or specific hallmarks) are not independent phenomena but are deeply intertwined nodes in this network. A decline in one area (e.g., mitochondrial function) places stress on others (e.g., increases genomic instability, triggers senescence), leading to a cascading collapse that manifests as what we call “aging.” My view on this is that the hallmarks in Viewpoint 1 are not siloed.

Interdependence of Hallmarks

  • Genomic instability can directly trigger cellular senescence.
  • Mitochondrial dysfunction leads to the production of reactive oxygen species (ROS) that can cause genomic instability.
  • Senescent cells secrete a cocktail of inflammatory proteins (the SASP), which drives inflammaging and alters intercellular communication.

Antagonistic Pleiotropy
While theory, there is a strong foundation for the network view. It posits that genes that are beneficial for development and reproduction in youth can have unselected, detrimental effects later in life. A prime example is the growth hormone/IGF-1/mTOR axis, which is critical for reaching maturity but whose continued high activity in later life accelerates aging by driving several hallmarks. This suggests aging is a byproduct of a system optimized for early, not late, life.

Resilience as a Biomarker
Researchers are increasingly focused on measuring the body’s ability to recover from a stressor (e.g., illness, injury) as a key indicator of biological age. This dynamic network resilience may be a more accurate measure of aging than any static biomarker.

The network failure view would frame the role of Apo(b) perfectly. Elevated Apo(b) is a significant perturbation to the network. Locally, it It destabilizes the vascular endothelial sub-network, leading to ASCVD. Systemically the chronic inflammatory response it triggers (inflammaging) is a massive stressor on the entire network. This systemic inflammation can exhaust the immune system, promote senescence in distant tissues, and contribute to insulin resistance. Thus, lowering Apo(b) does more than fix a local problem; it reduces a major source of systemic noise and stress, thereby increasing the resilience and stability of the entire physiological network. It calms a key inflammatory node, allowing the rest of the system to function better.

Is There a Best Way to Look at This Issue?
The most accurate and useful perspective is a synthesis of these two views. This avoids a false dichotomy and embraces the complexity of the biology. Aging is the progressive failure of a complex physiological network (Viewpoint 2), and the “Hallmarks of Aging” represent the most critical, interconnected nodes whose individual failures drive the overall system collapse (Viewpoint 1).

Therefore, an intervention can be, and often is, both. It is a disease-specific intervention because its most visible and measurable effect is on a particular pathophysiology (e.g., lowering Apo(b) reduces plaque formation). It is a geroprotective intervention because the node it targets (e.g., lipid-driven inflammation) is so deeply integrated into the larger network of aging that stabilizing it has beneficial, pleiotropic effects that enhance the resilience of the whole system. But it is also a powerful intervention against the process of aging by mitigating chronic inflammation, a core hallmark and a driver of network-wide instability. The distinction, while useful for regulatory and clinical purposes, is ultimately artificial from a biological standpoint.

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