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

DOI: 10.1016/j.cmet.2020.08.004
PubMed: PMID 32877690
PubMed Central: PMC8508957
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

Design	Longitudinal in vivo mouse lifespan and healthspan study with two independent replicated cohorts, plus in vitro senescence and immune sub-studies
Model	Middle-aged (18-month-old) C57BL/6 mice, both sexes; IMR-90 human fibroblasts for in vitro SASP work
Sample	182 mice total across two cohorts (cohort 1 n=90, cohort 2 n=93); roughly balanced by sex
Intervention	2% calcium alpha-ketoglutarate (CaAKG) supplemented into standard chow, starting at 18 months of age and continued for the rest of life
Duration	Life-long (until natural death); frailty index measured every 8 weeks; cytokine and immune endpoints at 24 months (6 months on treatment)
Endpoints	Primary — 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 is the paper that put calcium alpha-ketoglutarate (Ca-AKG) on the longevity map. Researchers at the Buck Institute for Research on Aging fed middle-aged mice (18 months old, roughly equivalent to a 60-year-old human) a diet supplemented with Ca-AKG for the rest of their lives and tracked what happened.

Female mice on Ca-AKG lived roughly 16 to 20 percent longer than untreated females — a large effect for a late-life intervention. Male lifespan showed a trend but did not reach statistical significance. In both sexes, the striking finding was reduced frailty: Ca-AKG-fed mice stayed healthier for longer, with less fur discolouration, less coat deterioration, straighter spines, better gait, and fewer age-related conditions. The technical description is that Ca-AKG compressed morbidity — the disease-free period lengthened relative to lifespan.

The mechanism the authors propose is anti-inflammatory: Ca-AKG-fed mice had lower circulating inflammatory cytokines and higher levels of IL-10-producing T cells, an anti-inflammatory immune population. In cell culture, Ca-AKG suppressed the inflammatory secretions from senescent cells (the "SASP") without necessarily killing those cells. The paper does not prove Ca-AKG works the same way in humans — that is what the ABLE and other ongoing trials are designed to test.

Key findings

Female median lifespan extended by 16.6% in cohort 1 and 19.7% at 90th-percentile survival in cohort 2 (cohort 1 p=0.04; cohort 2 p=0.037; pooled p=0.03).
Male lifespan showed no statistically significant extension (cohort 1 p=0.18; cohort 2 p=0.31; pooled p=0.17).
Frailty index reduced substantially in both sexes: area under the curve dropped 46% in females and 41% in males vs controls (treatment effect p<0.0001 for both sexes).
Specific frailty phenotypes significantly improved: fur colour, coat condition, dermatitis, gait disorder, kyphosis, body condition, and eye discharge.
Fur repigmentation restored: proportion of Dct+ (melanocyte-containing) hair follicles rose from roughly 40% in controls to roughly 60% in AKG-fed mice (p<0.05).
Plasma inflammatory cytokine panel (24 markers including eotaxin, IL-6, IL-1β, TNFα, IFNγ, CCL2, CCL5) suppressed in female AKG-fed mice at 24 months (paired t-test p<0.001); males showed non-significant trend.
IL-10 producing CD4+ and CD8+ splenic T cell frequencies increased in AKG-fed females (p=0.0215 and p=0.0028 respectively); no significant effect in males.
Tissue mRNA expression of p21 and p16 senescence markers reduced in liver, kidney, heart and skin of AKG-fed mice.
In IMR-90 fibroblasts induced to senesce, AKG suppressed SASP gene expression (IL-1α, IL-1β, IL-6, IL-8, CCL2, CXCL1, MMP-3) and lowered IL-6 secretion without reducing SA-β-galactosidase positivity — indicating senomorphic rather than senolytic action.

What this study can and cannot tell us

What this study can and cannot tell us:

Sexually dimorphic response — the statistically significant lifespan extension was confined to females; male lifespan showed only a trend. Any translation to humans has to reckon with this.
Late-onset intervention starting at 18 months of age was not compared to earlier initiation, so we cannot say whether starting earlier would give better or worse results.
The dramatic frailty index reduction is partly driven by animals that died relatively early; this compresses the frailty curve rather than proving that survivors were universally healthier for longer.
The IL-10 / anti-inflammatory mechanism is proposed and correlated but not causally proven — no IL-10 knockout or blockade experiment was performed in vivo.
Dose translation from mice to humans is not established. 2% CaAKG in mouse chow is a very high relative dose; the equivalent human dose is not calculable from this paper alone.
The authors' company involvement (Ponce de Leon Health, Gerostate Alpha, patent application) is disclosed and material. Four authors are shareholders or board members of the company that markets Rejuvant, a commercial Ca-AKG product.
Mouse aging biology does not perfectly mirror human aging; extrapolating a 16 to 20 percent lifespan extension to humans is not supported by these data.