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Reference topic 35: The Hallmarks of Aging

The hallmarks of aging: all twelve, explained

ProbableEvidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials.15 sources6 graded recommendationsTopic hub: Strength and boneTopic hub: Aging

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In January 2023, a review in Cell by Carlos López-Otín and four colleagues proposed twelve hallmarks of aging. Its abstract lists them: "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, and dysbiosis."1

Ten years earlier, the same senior authors had published a list of nine that organized the field.1

Mismatch card

The system

The cellular machinery of aging, named in 2023 as twelve hallmarks, from telomere attrition and disabled autophagy to chronic inflammation and dysbiosis.

What it expects

Muscles loaded most days, food that comes and goes, microbes, and stressors that end.

What it gets

Decades of low mechanical load, continuous food, and stress without resolution.

What happens in the gap

Strength falls away faster than age alone requires, while the processes that age cells run with fewer of the brakes the body evolved to apply.

The handrail

Build and keep strength, and take the other inputs from the chapters that own them (●●○)

Strength of evidence

●●○ Strength predicts survival in two large cohorts and two years of calorie restriction slowed one methylation clock by 2 to 3%, but no intervention has been shown to slow human aging itself.

What this topic covers

  • ·The Clock at the End of the Chromosome
  • ·Cells That Will Not Leave
  • ·The Recycling Machinery
  • ·A Clock You Can Read
  • ·The Brains in the Bolivian Lowlands
  • ·The Measure You Can Hold

The practical version is in the book: Chapter 16, Aging Well.

The handrail

Topic 40 holds the training doses. What follows is what this chapter's evidence supports on its own.

Each recommendation carries the strength of the evidence behind it. How the grades work.

  1. Build and keep strength

    ProbableEvidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials.

    Strength predicted lower all-cause and cancer mortality in 8,762 men independently of aerobic fitness,14 and grip strength stratifies risk across a large multinational cohort.15 No trial has randomized anyone to decades of lifting and counted the deaths, and none ever will, so the grade stops at probable. If you are new to loaded movement, or have a joint or heart condition, start under guidance.

  2. Measure strength, not your "biological age"

    ProbableEvidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials.

    A hand dynamometer or a rise from the floor (Topic 6) gives you a number tied to outcomes in cohort studies and to the clinical screening criteria for sarcopenia.16

  3. Take the other hallmark inputs from the chapters that own them

    Aerobic fitness (Topics 8 and 40), sleep (Topics 23 and 41) and social connection (Topics 29 and 42) each touch processes on the 2023 list, and each carries its own evidence and grade there.

  4. Calorie restriction as an anti-aging strategy

    EmergingEvidence grade: Emerging. Early, small, animal-only, or actively contested.

    Two years of attempted 25% restriction, achieved at about 12%, slowed one methylation clock by 2 to 3% and moved two others not at all.9 That is a real finding and not a demonstration of a longer or healthier life. Sustained restriction is not appropriate for people who are underweight, pregnant or breastfeeding, or who have a history of disordered eating. Anyone on medication for diabetes should not change their eating pattern without their clinician.

  5. Do not take senolytics outside a trial

    EmergingEvidence grade: Emerging. Early, small, animal-only, or actively contested.

    The only published senolytic experiment in humans that measured senescent cells enrolled nine people for three days and measured no health outcome.4 Dasatinib is a prescription cancer drug with real toxicity. This is not a supplement decision.

  6. Treat consumer biological-age tests as entertainment

    EmergingEvidence grade: Emerging. Early, small, animal-only, or actively contested.

    They will not tell you what to do, and whatever they might prompt is already in the handrail chapters.

The skeptic's corner

The case against this topic, from the research itself.

Several companies now sell "biological age" tests to consumers, built on clocks like Horvath's or DunedinPACE. Those clocks were developed and validated as research tools for comparing large groups. No evidence reviewed for this chapter shows that moving your personal score by changing your habits predicts anything about your health. Working for groups does not make a test precise for one person. Topic 43 has more on tracking a thing in place of changing it.

Fasting and autophagy is the clearest case of mechanism outrunning measurement. The yeast and mouse biology is solid. The human version cannot yet be tested, because nobody can measure it in a living person. Anyone who tells you their eating window is triggering autophagy is describing a hope.

Senolytics deserve both halves of the truth. The mechanism is real, and the pilot data are encouraging as proof of mechanism. But dasatinib is a cancer drug that can harm the blood and cause fluid retention, and quercetin is not inert. The human evidence still amounts to nine people, a few small early-phase trials and no clinical outcome. Trying them on yourself is a live safety problem, not a theoretical one.

One finding from the Tsimane is a warning posted over the whole field. Carriers of APOE4 (apolipoprotein E4), the gene variant most strongly linked to Alzheimer's risk in industrialized populations, showed better preserved cognition when their parasite burden was high. Non-carriers with a high parasite burden did worse.13 The same variant, read in a different environment, changed sign; Topic 37 takes up what that means for personal genetics. Any account of aging that treats the genome as the script and the environment as the staging has the relationship the wrong way round.

Terms this topic defines

Related topics

Sources cited above

  1. 1.López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2023). "Hallmarks of aging: An expanding universe." Cell, 186(2), 243-278. https://doi.org/10.1016/j.cell.2022.11.001 (the twelve-item list and the three admission criteria are quoted and paraphrased from the abstract; the paper also describes what it adds to the nine hallmarks the same senior authors proposed in 2013, namely disabled macroautophagy, chronic inflammation and dysbiosis. The three-tier grouping into primary hallmarks (damage), antagonistic hallmarks (responses to damage) and integrative hallmarks is the paper's own structure, carried over from the 2013 paper.)
  2. 13.Trumble, B.C., Stieglitz, J., Blackwell, A.D., Allayee, H., et al. (2017). "Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden." The FASEB Journal, 31(4), 1508-1515. (n=372.)
  3. 14.Ruiz, J.R., Sui, X., Lobelo, F., Morrow, J.R. Jr., et al. (2008). "Association between muscular strength and mortality in men: prospective cohort study." BMJ, 337, a439. https://doi.org/10.1136/bmj.a439 (8,762 men aged 20-82 at the Cooper Clinic, Dallas; 18.9 years mean follow-up, 165,251 person-years; 503 all-cause deaths, hazard ratios 0.72 (95% CI 0.58-0.90) middle third and 0.77 (0.62-0.96) upper third against the lower third; 199 cancer deaths, 0.72 (0.51-1.00) and 0.68 (0.48-0.97); associations persisted after adjustment for cardiorespiratory fitness. The cohort is predominantly white, middle-to-upper socioeconomic status and male.) (strength was measured as the one-repetition maximum on bench press and leg press, combined into an age-adjusted score and split into thirds)
  4. 15.Leong, D.P., Teo, K.K., Rangarajan, S., Lopez-Jaramillo, P., et al. (2015). "Prognostic value of grip strength: findings from the Prospective Urban Rural Epidemiology (PURE) study." The Lancet, 386(9990), 266-273. https://doi.org/10.1016/S0140-6736(14)62000-6 (the quoted description is the study's own framing; specific hazard ratios and participant counts have not been independently confirmed and are deliberately not stated here.)
  5. 16.Global Consensus for Sarcopenia (2024). Aging, 16(11), 9306-9308. https://doi.org/10.18632/aging.205919 (cited for the screening logic that low grip strength or slow gait speed, rather than muscle mass alone, defines the clinical entry point; specific diagnostic thresholds are not stated here.)
  6. 9.Waziry, R., Ryan, C.P., Corcoran, D.L., Huffman, K.M., et al. (2023). "Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial." Nature Aging, 3(3), 248-257. (n=220, two years, about 25% target restriction and about 12% achieved; DunedinPACE pace of aging slowed about 2-3%; no significant effect on PhenoAge or GrimAge.) (the trial is the second phase of CALERIE, called CALERIE-2)
  7. 4.Hickson, L.J., Langhi Prata, L.G.P., Bobart, S.A., Evans, T.K., et al. (2019). "Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease." EBioMedicine, 47, 446-456. https://doi.org/10.1016/j.ebiom.2019.08.069 (open-label pilot, n=9, mean age 68.7, mean eGFR 27.0 mL/min/1.73m²; adipose p16INK4A+ -35% p=0.001, p21CIP1+ -17% p=0.009, senescence-associated beta-galactosidase-positive -62% p=0.005; CD68+ macrophages -28%, crown-like structures -86%; skin p16INK4A+ -20%, p21CIP1+ -31%; circulating IL-1alpha, IL-6, MMP-9 and MMP-12 fell.) (dasatinib 100 mg a day with quercetin 1,000 mg a day for three days; biopsies eleven days after the last dose; the fall of more than half in fat was in cells staining for senescence-associated beta-galactosidase, the fall of nearly a third in skin was in p21-positive cells; senescent cells secrete inflammatory signals known as the senescence-associated secretory phenotype)

This topic carries 15 notes in the research manuscript; the 7 above are those behind the material on this page. Full source register.