Tier 3 — preclinical

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice

Azar Asadi Shahmirzadi, Daniel Edgar, Chen-Yu Liao, Yueh-Mei Hsu, Mark Lucanic, Arash Asadi Shahmirzadi, Christopher D. Wiley, Garbo Gan, Dong Eun Kim, Herbert G. Kasler, Chisaka Kuehnemann, Brian Kaplowitz, Dipa Bhaumik, Rebeccah R. Riley, Brian K. Kennedy, Gordon J. Lithgow
Cell Metabolism 2020 Volume 32, issue 3, pages 447–456.e6

Bibliography

PubMed
PMID 32877690
PubMed Central
PMC8508957
DOI
10.1016/j.cmet.2020.08.004
Funding
Funding for the study on Alpha-Ketoglutarate was provided by the National Institutes of Health (NIH) grant U01AG045844, the National Institute on Aging (NIA) grant R01AG051729, and the Larry L. Hillblom Foundation. Additional support came from The Weldon Foundation, the Navigage Foundation, and Ponce de Leon Health. You can view the full funding details in the published study in Cell Metabolism.
Competing interests
G.J.L. and M.L. are co-founders of Gerostate Alpha, a company aimed at developing drugs for aging, and are shareholders in Ponce de Leon Health. D.E. and Azar Asadi Shahmirzadi are shareholders in Ponce de Leon Health. B.K.K. is a board member and equity holder at Ponce de Leon Health. G.J.L., B.K., M.L., D.E., and Azar Asadi Shahmirzadi are named inventors on a preliminary patent application related to this discovery.

Study snapshot

DesignLongitudinal in vivo mouse lifespan and healthspan study with two independent replicated cohorts, plus in vitro senescence and immune sub-studies
ModelMiddle-aged (18-month-old) C57BL/6 mice, both sexes; IMR-90 human fibroblasts for in vitro SASP work
Sample182 mice total across two independent cohorts; approximately 45 ± 2 animals per sex/treatment group in each cohort
Intervention2% calcium alpha-ketoglutarate (CaAKG) supplemented into standard chow, starting at 18 months of age and continued for the rest of life
DurationLife-long (until natural death); frailty index measured every 8 weeks; cytokine and immune endpoints at 24 months (6 months on treatment)
EndpointsPrimary — median and maximum lifespan; Primary — 31-parameter total frailty index score; Secondary — individual frailty phenotypes (fur colour, coat condition, dermatitis, gait, kyphosis, tumours, hearing loss, piloerection, alopecia, body condition); Secondary — plasma inflammatory cytokines and chemokines (24-marker panel); Secondary — hair follicle melanocyte counts and fur repigmentation; Secondary — IL-10 producing CD4+ and CD8+ splenic T cell frequencies; Secondary — tissue mRNA expression of p21 and p16 in liver, kidney, heart, skin; Secondary — in vitro SASP genes and IL-6 secretion in senescent IMR-90 cells

What the study showed, in plain terms

This 2020 study tested calcium alpha-ketoglutarate (Ca-AKG) as a late-life intervention in C57BL/6 mice. Supplementation began at 18 months of age and continued for the remainder of life, while the investigators tracked survival, frailty and several inflammatory and senescence-related measures.

Female survival improved in both cohorts, but the size of the effect differed by cohort. In cohort 1, female median lifespan increased by 16.6% and 90th-percentile lifespan by 19.7%; in cohort 2, the corresponding increases were 10.5% and 8%. Male survival was not significantly extended. Frailty scores improved in both sexes.

The authors also reported lower inflammatory signaling and changes in senescence-associated markers, including suppression of the senescence-associated secretory phenotype in cell culture. These findings are important preclinical evidence, but they do not show that Ca-AKG extends lifespan in humans.

Key findings

  • Female lifespan increased in both cohorts, but effect size differed: cohort 1 median lifespan +16.6% and 90th-percentile lifespan +19.7%; cohort 2 median lifespan +10.5% and 90th-percentile lifespan +8%.
  • Male survival was not significantly extended by Ca-AKG.
  • Frailty index area under the curve was reduced in both sexes, with large treatment effects reported across the longitudinal frailty measurements.
  • Several individual frailty phenotypes improved, including coat condition, dermatitis, gait, kyphosis and body-condition measures.
  • Female mice showed lower circulating inflammatory cytokine signals and increased frequencies of IL-10-producing CD4+ and CD8+ T cells in the reported immune analyses; male inflammatory effects were less consistent.
  • Expression of senescence-associated markers including p21 and p16 was lower in several tissues in treated mice.
  • In senescent IMR-90 fibroblasts, AKG suppressed multiple SASP genes and IL-6 secretion without clearly eliminating senescent cells, supporting a senomorphic rather than senolytic interpretation.

What this study can and cannot tell us

What this study can and cannot tell us:

  • The statistically significant survival effect was sex-dependent: female survival improved, whereas male survival did not show a significant extension.
  • The intervention started at 18 months of age, so the study does not establish how earlier or later initiation would change the result.
  • Frailty outcomes are informative but are influenced by survival and repeated-measures structure; they should not be interpreted as proof that every treated survivor was uniformly healthier.
  • The proposed anti-inflammatory and IL-10-related mechanism is supported by associated immune and cell-culture findings but was not established as the sole causal pathway in vivo.
  • The mouse dietary exposure cannot be converted directly into a validated human longevity dose from this study alone.
  • Multiple authors disclosed commercial and patent interests involving Ponce de Leon Health and/or Gerostate Alpha; several were shareholders, founders, board members or named inventors on a related patent application.
  • Mouse lifespan findings do not establish that Ca-AKG extends human lifespan.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology