Is Our Gero Strategy Aimed More at Fatal Disease Prevention or Slowing a Theoretical Clock

#1

This table is illustrative along a few dimensions.

Agent Primary mechanism Aim it mostly serves Human mortality/lifespan evidence
Statins / PCSK9i / ezetimibe ApoB/LDL lowering Disease mitigation (ASCVD) Strong RCT
Antihypertensives BP reduction Disease mitigation (stroke/HF/CKD) Strong RCT
Low-dose aspirin Antiplatelet Disease mitigation (CV/CRC) RCT — net null/harm in healthy elderly (ASPREE)
Omega-3 TG↓, anti-inflammatory Disease mitigation (CV) Mixed (VITAL null, REDUCE-IT+ vs STRENGTH−)
GLP-1 RAs (semaglutide, tirzepatide) Incretin/weight/metabolic Disease mitigation (metabolic/CV/renal) Strong and expanding (SELECT, all-cause signal)
SGLT2i (empagliflozin etc.) Glucosuric/metabolic/ketone shift Disease mitigation → emerging gero Strong RCT + male-mouse ITP lifespan
Vitamin D Deficiency correction Disease mitigation (bone; hard endpoints null) Mostly null
Metformin AMPK↑, mild complex-I inhibition, mTOR↓, gluconeogenesis↓ Crossover (TAME frames as geroprotector) Human lifespan unproven; founding diabetic-mortality signal likely confounded
Acarbose α-glucosidase inhibition, postprandial glucose blunting Crossover ITP male lifespan; no human gero data
17α-estradiol Non-feminizing metabolic/inflammatory Crossover ITP male lifespan; no human data
Rapamycin mTORC1 inhibition → autophagy, senescence, proteostasis Aging clock Strongest cross-species animal data (ITP, late-life onset); human lifespan absent, safety/immune data emerging (PEARL)
Senolytics (D+Q, fisetin) Clear senescent cells Aging clock Early human trials (IPF, DKD, bone)
NAD⁺ precursors (NR, NMN) Sirtuin/mito/PARP-DNA-repair axis Aging clock Raises NAD⁺; downstream clinical benefit unproven
Sirtuin activators (resveratrol) SIRT1 Aging clock Poor bioavailability; human ~null
Spermidine Autophagy induction Aging clock Epidemiological mortality association only
Taurine Multi (mito, inflammation) Aging clock One 2023 mouse/worm lifespan paper; human unvalidated
GlyNAC (glycine + NAC) Glutathione/oxidative Aging clock Small human trials

First, the crossover traffic is one-directional. Every agent in the middle band is a disease drug being promoted into the geroprotector category. Metformin, acarbose, SGLT2i, arguably the GLP-1s are in this category. Essentially no pure clock supplement has earned its way into the validated-disease category. NR/NMN, resveratrol, spermidine have been in the clock column for a decade. The directionality is the evidence runs from “proven against disease to maybe also gero,” never the reverse.

Second, within the clock column, adoption tracks evidence, not theory. The one genuine clock-drug that clock-believers are most likely to take is rapamycin because it is the one with robust, late-onset, cross-species animal lifespan data from the ITP. In contrast, the NAD⁺/sirtuin material, which is theory-rich but human-evidence-poor has mixed adoption and NAD might actually be falling in favor (I’m uncertain of that). So, even the people committed to the clock theory are, basing their behavior on evidence.

Third, people are mostly acting on effects they can measure and manage to success: ApoB, Lp(a), HbA1c, BP, hsCRP are examples. There is no validated, intervention-responsive, actionable way to measure and manage “rate of aging.” Epigenetic clocks are noisy and have not been shown to move lifespan when you move the clock. So, even if we believe an aging clock exists, we demonstrate rationality by putting serious efforts into diseases of aging mitigation.

One other somewhat orthogonal thought. The crossover interventions are almost entirely at the nutrient-sensing axis (mTOR, AMPK, insulin/IGF-1, glucose). These pathways are arguably the modulators of much age-related disease risk. Metformin, acarbose, SGLT2i, rapamycin, and caloric restriction all converge on this point. My opinion is that these two paths – prevent disease/slow clock are least separable on this point. This could be taken as evidence that they are part of a yet-to-be discovered unification.

2 Likes
#2

Very thought provoking post, thanks for sharing.

True, and that may be because prevention is the best we can currently do, or because lifespan extension necessarily involves prevention.

True, this could be just a failure of geroscience to find the right disease, or it just that they don’t matter.

1 Like
#3

This is a fundamental distinction that many people - including biohackers on this site! - for some reason don’t seem to grasp. There are two interventions to postpone death: (1)prevention of life shortening and (2)life extension. There is a natural max lifespan for every species. In a standard mouse strain, max lifespan is somewhere around the 900 day mark. If the mouse is suffering from disease that is going to kill it at 500 days then drug X which cures the disease only allows it to live normally to 900 days - it normalizes lifespan, it prevents the shortening of life. Now, an intervention, say drug Y which allows the mouse to live much past 900 days, say, 1200 days, that’s a life extending intervention. Those are not the same thing.

Now, one could say that all physiological deaths which are not due to accidents are caused by the failure of the weakest link. That weakest link can appear at any age. A childhood fatal disease appears early. Many diseases appear later in life. But merely taking care of that weak link is always preventing the shortening of life. What happens if you take care of all weak links - you reach your max lifespan and all systems collapse at once, it’s like a chain where every single link has simultaneously worn to a breaking point. At that point, the only intervention which will delay death is if you slow down the “wearing” of the links - slow down aging. Every single life extending intervention necessarily is an intervention that addresses the aging process itself - not a pathology, but the aging process itself. And that too will have a limit which is the inherent design (which only genetic re-design can modify).

The distinction is: drugs which prevent early death are often curative. But life extending drugs don’t cure anything - they slow down the aging process. They might incidentally alleviate conditions or prevent pathologies, but that’s an incidental effect. Rapamycin doesn’t specifically cure anything. CR doesn’t cure anything. Although both can prevent some pathologies or ameliorate them if already present.

That is why we do max lifespan studies. Any drug/intervention in mice which allows a more - or all - of the cohort to live to 900 days is simply preventing life shortening. And if we can make the cohort live to, say 1200 days, well, that’s life extension which you can only reach by slowing the inherent rate of aging for that species. Because that clock is different for different species - a mouse ages and dies within a roughly 3 year span, whereas another rodent of the same size, the naked molerat dies somewhere around 40 years. If you compare the NMR and the mouse tissues, you can clearly see that the rate of senescence is different. We are hoping to affect that clock - and we can, in the mouse, by whatever percentage - 70%, perhaps 100%. But to get more than that, we will need to reorganize the entire genetic code, without such a redesign a mouse will never reach a NMR lifespan, no matter how excellent the intervention/drug is - there’s a design limitation.

Humans naturally tap out somewhere between 120-130 year lifespan. It is probably feasible to slow aging enough to extend that to perhaps 150 or so. To go any further, we need to redesign the genetic code. But to even reach that theoretical 150, we need to navigate an obstacle course, weak links that will result in death at 1, 30, 70, 85, 105, 119 or any other point before our stretch goal. That’s what those other drugs do - clear the obstacle course: statins, BP drugs, vaccines etc. - they won’t extend lifespan, but might extend healthspan.

These two are not mutually exclusive in strategies to delay death. We need both - the weak-link fixing life shortening drugs and the age-slowng life extending drugs. You can’t just take the latter, because your weak links will kill you before you can reap the full benefits of slowing the aging process.

There can even be a paradox - a drug both slows down the aging process AND kills you prematurely. Matt Kaebarlien pointed that out. You can have a drug which slows down the aging process, but at the cost of immunity, and that works fine in the lab, the mouse lives 1200 days. But take that same mouse on that drug and put it in an environment unprotected from pathogens and it dies at 500 days. You then examine the tissues of the mouse and see that they have only aged biologically to about 200 days. The drug slowed down the aging and killed the mouse. This illustrates the stark distinction between aging and life extension and the prevention of premature death. WE NEED BOTH, because almost all of us have some weak link that is looking to prevent us from even reaching the max biological lifespan for our species - 120-130 years.

And that’s why my prescription drug stack looks like this:

1)Pitavastatin - addresses weak links
2)Bempedoic acid - addresses weak links
3)Ezetimibe - addresses weak links
4)Telmisartan - addresses weak links

5)Empagliflozin - addresses weak links + ?extends lifespan?

6)Rapamycin - ?extends lifespan?

And of course all my supplements all address weak links.

We need BOTH simultaneously.

Incidentally, diet, exercise and lifestyle definitely address only weak links. Exception: if you include calories as part of “diet” then CR obviously might qualify as ?life extension? and for lifestyle - CE (sustained cold exposure therapy - this is not any silly cold plunges!) - also might qualify as ?life extension?. One thing which in no way no how extends lifespan is exercise, although it most certainly can prevent life shortening.

#4

I think almost everyone understands this distinction well. I and others have stated it and taken opinions on it on more than one occasion. Broadly, the distinction characterizes a family of perspectives some of which appear incommensurable at this point while others appeal the possibility of discovering a unifying underlying thesis.

1 Like
#5

Some do, some don’t. I’m not going to name names, but I have had long arguments here with people who claim that exercise or statins by merely preventing a heart attack qualifies them to be “life extending” - really just a misundrestanding of how these terms are used in common language vs defined in specialized jargon used in biology. Folks will essentially claim a seat belt is a life-extending intervention. I’ve had too many arguments here to assume that this is a widely understood distinction.

1 Like
#6

To me, practically, this currently falls into a “distinction without a difference” . Mostly. The difference will be starker when we get better gero drugs.

1 Like
#7

I disagree with the idea of appropriating one arm of this field under the label, “extending lifespan.,” especially given how clear it was to me that emergency surgery for a nearly ruptured appendix at age 23, extended my lifespan. A more accurate label would center on slowing the processes of aging such that – hypothetically – something that would likely have taken your life at 75 years in the absence of Elixir 99, ends up taking it at age 99. This is a somewhat more palatable label but, even with that clarification, the notion is a conceptual (meaning in this case, inferential) mess.

The notion of slowing the processes of aging and therefore the initiation and progression of processes of dying is necessarily a population construct. It has no non-trivial meaning at the individual level. This is yet another reason not to make too much of this distinction. Exercise and fasting – by the way – seem to delay the initiation and progression of processes of dying.

If we push this distinction to its logical extreme, it collapses. For example, we may learn that rapamycin – a leading candidate for slowing the clock – may do its work by strengthening the immune system and slowing it decline, meaning that it will arrest the progression of specific diseases that kill us. Sound familiar? It should except that it is the foundation argument under the other arm of this distinction.

#8

I agree that in terms of its effect on my current course of action, the disease v. clock distinctions are inconsequential. I also believe that the distinctions are not especially important to the scientists actively engaged in gero research. The issue and its distinctions are mostly debate topics in among we gero advocates. Sometimes the emerging understanding is useful.