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Other Theories

Short, plain‑English summaries of additional aging frameworks beyond the seven core pages. Each item notes what the theory claims, recent progress, and what would most decisively test it.

Hyperfunction / Quasi‑Program (mTOR)

  • What it says: Aging partly comes from growth programs running too long (mTOR “run‑on”); dialing them down can slow decline.
  • What works (in animals): Late‑life rapamycin extends mouse lifespan and healthspan, including starts at ~20 months†. Low‑dose TORC1 inhibition improved flu vaccine responses in older adults†.
  • Criticisms/caveats: Effects depend on dose/schedule/sex/strain; high/continuous dosing can impair glucose handling (intermittent or combo regimens help)††. Benefits may be driven partly by anticancer effects (median > max lifespan gains). Human lifespan data are absent; a dog lifespan/healthspan trial is ongoing†.
  • How it stacks with other theories: Best used with complementary levers—
    • SENS‑style repair (fixes existing lesions) while mTOR dialing reduces “run‑on” damage.
    • Senescent‑cell clearance to cut SASP/inflammation, then maintain with rapamycin.
    • Proteostasis/autophagy boosters (lysosome/TFEB or chaperones) for housekeeping beyond mTOR.
    • Systemic milieu/microbiome resets to improve the top‑down environment.
  • What would convince skeptics: In normal aged animals, intermittent TORC1‑preferential regimens that (a) lower mortality and improve multi‑organ function, (b) show hazard‑shape changes beyond anticancer delay, and (c) translate in dogs—with acceptable safety.
  • Crucially: This is a complementary axis, not a complete, all‑causes theory. It doesn’t preclude other mechanisms (e.g., SENS repair, epigenetic reprogramming, senolytics, systemic milieu/microbiome, bioelectric control, pathogen context); stacks are the realistic path to large gains.

Metabolic Stress / NAD Resilience (Brenner)

  • What it says: Aging reflects cumulative metabolic/inflammatory stress and loss of resilience; the epigenome/transcriptome mostly mirror current state. Brenner emphasizes the NAD system as a stress‑sensitive axis — support it and other resilience pathways to improve function in context, but don’t equate expression shifts with “age reversal.”
  • Recent progress: Quantitative NAD metabolomics reveals stress‑induced perturbations; precursor strategies (e.g., NR) show protection in disease/insult models. However, organism‑level lifespan extension in normal animals isn’t established.
  • Critique of reprogramming: “Making expression look young” (e.g., with hormones) doesn’t prove lower mortality or durable function gains†.
  • Key tests: In normal aged animals, show that (a) metabolic stress normalization or NAD‑targeted interventions lower hazard and improve multi‑organ function with good safety; and (b) for epigenetic resets, benefits extend beyond transcript/clock shifts to clear hazard reductions.
  • References: Brenner Lab overview on NAD metabolism†.

Somatic Mutation / Mosaicism

  • What it says: DNA “letter” changes build up in tissues, forming mutant clones that impair function and raise disease risk; this burden scales with lifespan and cell turnover.
  • Recent progress: Single‑cell and bulk sequencing show age‑related mutation/clonal expansion in many tissues (e.g., blood CHIP). Cross‑species work links mutation rates with lifespan.
  • Key tests: Reducing mutation load or culling harmful clones (editing, replacement) should lower hazard and restore function in ways not explained by other mechanisms.
  • Sources: Cagan et al., Nature 2022 (10.1038/s41586-022-04545-8); Martincorena et al., Science 2015; Vijg reviews.

Senescent Cells (SASP)

  • What it says: Senescent cells accumulate and secrete inflammatory factors (SASP) that disrupt tissues. Clearing them improves healthspan.
  • Recent progress: Genetic ablation and senolytics improve multiple functions in mice; early human trials show signals in specific indications, though results are mixed by drug/dose and disease.
  • Key tests: In normal aged animals, do senolytics lower mortality and improve multi‑organ function with acceptable safety, and how do effects compare to epigenetic resets or mTOR inhibition?
  • Sources: Baker et al., Nature 2011 (10.1038/nature10600) and 2016; Xu et al., Nat Med 2018 (10.1038/s41591-018-0092-9).

Proteostasis Collapse (Chaperones, Autophagy, Lysosomes)

  • What it says: With age, cells lose the ability to fold, clear, and recycle proteins; misfolded/aggregated proteins drive dysfunction.
  • Recent progress: Broad evidence across species; interventions that boost chaperones or autophagy (e.g., heat‑shock pathways, lysosomal function) improve stress resistance and some age phenotypes.
  • Key tests: Durable, multi‑tissue restoration of proteostasis should reduce functional decline and hazard independent of other pathways.
  • Sources: Labbadia & Morimoto, Annu Rev Biochem 2015 (10.1146/annurev-biochem-060614-033955); Hipp/Kasturi/Hartl, Physiol Rev 2019 (10.1152/physrev.00040.2018).

Systemic Milieu / Parabiosis

  • What it says: Blood‑borne factors powerfully push tissues toward younger or older states. Changing the circulating environment rejuvenates function.
  • Recent progress: Heterochronic parabiosis, plasma fractionation, and “neutral blood exchange” improve multiple tissue readouts in mice. Human plasma exchange/FMT studies hint systemic leverage but need larger trials.
  • Key tests: In normal aged animals (and eventually humans), does modifying the milieu alone drive broad, durable gains in function/hazard vs. local tissue interventions?
  • Sources: Conboy et al., Nature 2005 (10.1038/nature03260); Villeda et al., Science 2014 (10.1126/science.1251141); Rebo et al., Nat Commun 2016 (10.1038/ncomms13363).

Microbiome / Inflammaging

  • What it says: Age‑shifted gut ecosystems amplify chronic inflammation and metabolic dysfunction; restoring a youthful microbiome improves resilience.
  • Recent progress: Microbiome transplants extend lifespan in short‑lived fish and improve metabolic markers in mammals; human FMT is established for infection and under study for aging‑relevant endpoints.
  • Key tests: Controlled microbiome resets that deliver durable, systemic function gains and hazard reduction beyond diet/weight effects.
  • Sources: Franceschi et al., Nat Rev Endocrinol 2018 (10.1038/s41574-018-0059-4); Smith et al., eLife 2017 (10.7554/eLife.27014).

Transposable Elements (TE) Derepression

  • What it says: Loss of TE silencing (e.g., LINE‑1) with age triggers innate immunity, DNA damage, and senescence; blocking TE activity reduces these signals.
  • Recent progress: TE activity rises in aged/senescent cells; reverse‑transcriptase inhibitors reduce inflammation and senescence markers in models.
  • Key tests: TE suppression lowers hazard and restores function broadly in normal aged animals, beyond effects explained by senescence or proteostasis alone.
  • Sources: Nature 2019 (10.1038/s41586-018-0784-9) on L1‑IFN in senescence; follow‑up RT‑inhibitor studies.

Membrane Pacemaker (Lipid Peroxidation)

  • What it says: Species with more peroxidation‑resistant membrane lipids tend to live longer; membrane composition sets metabolic pace and oxidative damage risk.
  • Recent progress: Strong comparative biology; interventional membrane remodeling is emerging (diet/genetic), but definitive lifespan tests are limited.
  • Key tests: Directly shifting membrane composition in mammals should change hazard/function independent of other pathways.
  • Sources: Hulbert AJ, Integr Comp Biol 2005 (10.1093/icb/45.5.475).

Hypothalamic / Neuroendocrine Control

  • What it says: The hypothalamus orchestrates systemic aging via inflammation, microglia, and hormones (e.g., GnRH). Tweaks here ripple body‑wide.
  • Recent progress: Rodent studies link hypothalamic inflammation and stem‑cell dynamics to aging; hormonal interventions show partial rescue.
  • Key tests: Selective, safe modulation of hypothalamic pathways that broadly lowers hazard and restores multi‑organ function.
  • Sources: Zhang et al., Nature 2013 (10.1038/nature12143) and follow‑ups.

Telomere Attrition

  • What it says: Telomere shortening and damage drive replicative limits and senescence; telomerase or telomere protection can restore capacity in some contexts.
  • Recent progress: Telomerase gene therapy extends lifespan in mice without increasing cancer in specific settings; human work focuses on safety and disease targets.
  • Key tests: Safe, targeted telomere restoration that improves function and lowers hazard in normal aged mammals.
  • Sources: de Jesus et al., EMBO Mol Med 2012 (10.1002/emmm.201200245); reviews by Blackburn/Greider/Szostak field.