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Geroprotector

From Wikipedia, the free encyclopedia

A geroprotector aims to affect the root cause of aging and age-related diseases, and thus prolong the life span of animals.[1][2] Some possible geroprotectors include melatonin,[3] carnosine,[4] metformin,[5] rapamycin,[6] nicotinamide mononucleotide (NMN),[7] delta sleep-inducing peptide,[8]glycine,[9] and psilocin.[10]

Geroprotectors could belong to multiple classes, depending on which of the hallmarks of aging they influence.[11][12]

The distinction between geroprotectors and senotherapeutics is an evolving area of aging research. Geroprotectors broadly aim to target multiple mechanisms of aging, prolonging lifespan and healthspan by addressing the fundamental causes of aging. Senotherapeutics, on the other hand, are a subset of therapies that specifically target senescent cells, which are dysfunctional cells that accumulate with age and contribute to inflammation and age-related diseases.[13]

Research

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In geroscience, drugs proposed to slow ageing are often called gerotherapeutics.[14] These compounds act on the hallmarks of aging as well as on a specific disease, aiming to benefit several age-related conditions at once.[14] As of 2022, the only accepted means of targeting ageing in people were diet and exercise.[14] At that time, drug regulators did not recognise outcomes based on targeting ageing as a route to approval.[14] These regulators included the US Food and Drug Administration and the European Medicines Agency.[14]

mTOR inhibitors

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Several research groups have tested the mTORC1 inhibitor rapamycin for its effect on lifespan in mice.[15] The first was a 2009 study by the National Institute on Aging's Interventions Testing Program.[15] It found that rapamycin lengthened the lives of genetically diverse mice.[15] Unlike caloric restriction, rapamycin remained effective when started at 20 months of age, roughly equivalent to a 60-year-old person.[15] Rapamycin has side effects, including immunosuppression, raised blood lipids and raised blood sugar.[15] These have made researchers cautious about its use in people and have slowed clinical trials of mTOR inhibitors for age-related disease.[15]

Metformin

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The diabetes drug metformin has been associated with lower mortality in clinical and observational studies.[14] It has also been associated with lower rates of several age-related diseases, including cardiovascular disease, cancer, Alzheimer's disease and mild cognitive impairment.[14] Geroscientists designed the Targeting Aging with Metformin (TAME) trial as a double-blind, placebo-controlled study.[14] Its main outcome is how long participants go before a cardiovascular event, cancer, cognitive decline, dementia or death.[14] TAME was also meant to serve as a model for later trials of other approved drugs repurposed against ageing.[14]

NAD+ precursors

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The nicotinamide adenine dinucleotide (NAD+) precursors most often tested in people are nicotinamide riboside and nicotinamide mononucleotide.[16] Nicotinamide riboside is sometimes combined with pterostilbene.[16] A 2023 review of oral supplementation trials found that these compounds appear safe and well tolerated.[16] They can raise levels of NAD+ and related metabolites in several tissues.[16] However, the trials have mostly been small and have used widely varying doses and durations.[16] Several randomized controlled trials found that nicotinamide riboside did not improve insulin sensitivity, energy expenditure or exercise capacity.[16]

Senolytics

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Senolytics, drugs that selectively remove senescent cells, were first described in 2015.[17] Early candidates included dasatinib, a cancer drug in clinical use since 2006.[17] They also included the plant flavonoids quercetin and fisetin, which occur in fruit and other foods.[17] Positive results in animal studies led to early-phase human trials, some of which have reported results.[17] A 2022 review advised that senolytics should not be recommended to prevent or treat disease, in clinical practice or over the counter.[17] It said this should hold until carefully monitored, rigorous trials show them to be safe and effective.[17]

See also

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References

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  1. ↑ Alexey Moskalev, Elizaveta Chernyagina, Anna Kudryavtseva & Mikhail Shaposhnikov (2017). "Geroprotectors: A Unified Concept and Screening Approaches". Aging and Disease. 8 (3): 354–363. doi:10.14336/AD.2016.1022. PMC 5440114. PMID 28580190.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ↑ Alexey Moskalev, Elizaveta Chernyagina, João Pedro de Magalhães & Alex Zhavoronkov (2015). "Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease". Aging. 7 (9): 616–628. doi:10.18632/aging.100799. PMC 4600621. PMID 26342919.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ↑ Anisimov, VN; Popovich, IG; Zabezhinski, MA; Anisimov, SV; Vesnushkin, GM; Vinogradova, IA (2006). "Melatonin as antioxidant, geroprotector and anticarcinogen". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1757 (5–6): 573–89. doi:10.1016/j.bbabio.2006.03.012. PMID 16678784.
  4. ↑ Boldyrev, AA; Stvolinsky, SL; Fedorova, TN; Suslina, ZA (2010). "Carnosine as a natural antioxidant and geroprotector: From molecular mechanisms to clinical trials". Rejuvenation Research. 13 (2–3): 156–8. doi:10.1089/rej.2009.0923. PMID 20017611.
  5. ↑ Bulterijs, S (2011). "Metformin As a Geroprotector". Rejuvenation Research. 14 (5): 469–82. doi:10.1089/rej.2011.1153. PMID 21882902. S2CID 40645408.
  6. ↑ Dumas, Sabrina N; Lamming, Dudley W (2020-01-01). "Next Generation Strategies for Geroprotection via mTORC1 Inhibition". The Journals of Gerontology: Series A. 75 (1): 14–23. doi:10.1093/gerona/glz056. ISSN 1079-5006. PMC 6909887. PMID 30794726.
  7. ↑ Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice, Cell Metabolism 24, 795–806, December 13, 2016 ª 2016 Elsevier Inc.
  8. ↑ Bondarenko, TI (2011). "Mechanism of delta-sleep inducing peptide geroprotective activity". Adv Gerontol. 24 (1): 80–92. PMID 21809625.
  9. ↑ Soh J, Raventhiran S, Lee JH, Lim ZX, Goh J, Kennedy BK, Maier AB (February 2024). "The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review". GeroScience. 46 (1): 219–239. doi:10.1007/s11357-023-00970-8. PMC 10828290. PMID 37851316.
  10. ↑ Kato, Kosuke; Kleinhenz, Jennifer M.; Shin, Yoon-Joo; Coarfa, Cristian; Zarrabi, Ali J.; Hecker, Louise (2025-07-08). "Psilocybin treatment extends cellular lifespan and improves survival of aged mice". npj Aging. 11 (1): 55. doi:10.1038/s41514-025-00244-x. ISSN 2731-6068. PMC 12238350. PMID 40628762.
  11. ↑ Moskalev, Alexey; Chernyagina, Elizaveta; Kudryavtseva, Anna; Shaposhnikov, Mikhail (May 2017). "Geroprotectors: A Unified Concept and Screening Approaches". Aging and Disease. 8 (3): 354–363. doi:10.14336/AD.2016.1022. ISSN 2152-5250. PMC 5440114. PMID 28580190.
  12. ↑ Moqri, Mahdi; Herzog, Chiara; Poganik, Jesse R.; Justice, Jamie; Belsky, Daniel W.; Higgins-Chen, Albert; Moskalev, Alexey; Fuellen, Georg; Cohen, Alan A.; Bautmans, Ivan; Widschwendter, Martin; Ding, Jingzhong; Fleming, Alexander; Mannick, Joan; Han, Jing-Dong Jackie (2023-08-31). "Biomarkers of aging for the identification and evaluation of longevity interventions". Cell. 186 (18): 3758–3775. doi:10.1016/j.cell.2023.08.003. ISSN 0092-8674. PMC 11088934. PMID 37657418.
  13. ↑ Al-Naggar, Iman M. A. (24 October 2020). "Senolytics: Targeting Senescent Cells for Age-Associated Diseases". Current Molecular Biology Reports. 6 (4): 161–172. doi:10.1007/s40610-020-00140-1. PMC 7992369. PMID 33777657.
  14. 1 2 3 4 5 6 7 8 9 10 Kulkarni AS, Aleksic S, Berger DM, Sierra F, Kuchel GA, Barzilai N (April 2022). "Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization". Aging Cell. 21 (4) e13596. doi:10.1111/acel.13596. PMC 9009114. PMID 35343051.
  15. 1 2 3 4 5 6 Mannick JB, Lamming DW (June 2023). "Targeting the biology of aging with mTOR inhibitors". Nature Aging. 3 (6): 642–660. doi:10.1038/s43587-023-00416-y. PMC 10330278. PMID 37142830.
  16. 1 2 3 4 5 6 Freeberg KA, Udovich CC, Martens CR, Seals DR, Craighead DH (December 2023). "Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 78 (12): 2435–2448. doi:10.1093/gerona/glad106. PMC 10692436. PMID 37068054.
  17. 1 2 3 4 5 6 Chaib S, Tchkonia T, Kirkland JL (August 2022). "Cellular senescence and senolytics: the path to the clinic". Nature Medicine. 28 (8): 1556–1568. doi:10.1038/s41591-022-01923-y. PMC 9599677. PMID 35953721.
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