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.