Will you live to 120? · Sources and Further Reading

Chapter 4 — Nutrient sensing

Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual Review of Physiology. — The reframing of senescence from a curiosity into a driver of aging.

Coppé, J.-P., et al. (2008). Senescence-associated secretory phenotypes… PLoS Biology. — The SASP, characterized.

Baker, D.J., et al. (2011). Clearance of p16^Ink4a-positive senescent cells delays ageing-associated disorders. Nature. — and Baker, D.J., et al. (2016). Naturally occurring p16^Ink4a-positive cells shorten healthy lifespan. Nature. — The INK-ATTAC mice: clearing senescent cells rejuvenates, first in a progeroid model, then in naturally aged mice.

Xu, M., et al. (2018). Senolytics improve physical function and increase lifespan in old age. Nature Medicine. — The causal complement to the clearance experiments: transplanting small numbers of senescent cells into young mice induces physical dysfunction and spreads senescence — and senolytics reverse it.

Zhu, Y., et al. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. — The first senolytics (dasatinib + quercetin), derived from the anti-apoptotic-pathway logic.

Demaria, M., et al. (2014). An essential role for senescent cells in optimal wound healing. Developmental Cell. — Why senescence is beneficial in its acute form — the basis for the “don’t clear all of them” caution.

Hickson, L.J., et al. (2019). Senolytics decrease senescent cells in humans… EBioMedicine. — First evidence that senolysis is achievable in people (in diabetic kidney disease).

Williams, G.C. (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution. — Medawar, P.B. (1952). An Unsolved Problem of Biology. — and Kirkwood, T.B.L. (1977). Evolution of ageing. Nature. — The three classic evolutionary theories of why aging exists (antagonistic pleiotropy, mutation accumulation, disposable soma).

(The Unity Biotechnology UBX0101 osteoarthritis Phase 2 result is documented in the company’s 2020 disclosures and the trial record rather than a primary paper.)

Chapter 4 — Nutrient sensing

Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature. — The worm that converted aging from fate into a regulated mechanism.

Harrison, D.E., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. — The Interventions Testing Program result: the field’s most reproducible drug, working even when started in old age.

McCay, C.M., Crowell, M.F., & Maynard, L.A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition. — The origin of caloric restriction.

Colman, R.J., et al. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. — Mattison, J.A., et al. (2012). Impact of caloric restriction on health and survival in rhesus monkeys. Nature. — and Mattison, J.A., et al. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature Communications. — The two famous monkey studies that appeared to contradict each other, and the joint reanalysis that resolved them — the chapter’s “compared to what?” set-piece. Read all three together.

Howitz, K.T., et al. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. — Baur, J.A., et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature. — and Pacholec, M., et al. (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. Journal of Biological Chemistry. — The rise and fall of resveratrol: the claims, and the assay-artifact debunk.

Rajman, L., Chwalek, K., & Sinclair, D.A. (2018). Therapeutic potential of NAD-boosting molecules. Cell Metabolism. — The case for NAD⁺ precursors, from a leading proponent — read critically.

Holzenberger, M., et al. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. — and Willcox, B.J., et al. (2008). FOXO3A genotype is strongly associated with human longevity. PNAS. — The insulin/IGF and FOXO pathway, from worm to mouse to human centenarian.

Waziry, R., et al. (2023). Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults (CALERIE). Nature Aging. — Human caloric restriction slowing a pace-of-aging clock.

Barzilai, N., Crandall, J.P., Kritchevsky, S.B., & Espeland, M.A. (2016). Metformin as a tool to target aging. Cell Metabolism. — The rationale for the TAME trial.

Chapter 5 — Mitochondria

Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. Journal of Gerontology. — and Harman, D. (1972). The biologic clock: the mitochondria? Journal of the American Geriatrics Society. — The free-radical theory and its mitochondrial refinement, in the originator’s own words.

McCord, J.M., & Fridovich, I. (1969). Superoxide dismutase: an enzymic function for erythrocuprein. Journal of Biological Chemistry. — The discovery that cells have dedicated antioxidant machinery.

The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994). The effect of vitamin E and beta carotene on the incidence of lung cancer… New England Journal of Medicine. — and Omenn, G.S., et al. (1996). Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease (CARET). New England Journal of Medicine. — The two trials in which an antioxidant given to prevent lung cancer increased it. The most important data in the chapter.

Klein, E.A., et al. (2011). Vitamin E and the risk of prostate cancer (SELECT). JAMA. — and Bjelakovic, G., et al. (2007). Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. JAMA. — More of the antioxidant graveyard, and the meta-analysis showing no benefit and some harm.

Ristow, M., et al. (2009). Antioxidants prevent health-promoting effects of physical exercise in humans. PNAS. — The elegant experiment showing antioxidants abolish the benefits of exercise — mitohormesis in action.

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