#1

Metabolite signatures of chronological age, aging, survival, and longevity 2024

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Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.

EL = extreme longevity

We identified four groups of metabolites (Figure 5B) that were associated with age, EL, and mortality risk. Signatures B1 and B2 showed patterns consistent with a damaging effect of aging (concordant directions of effect with age, EL, and mortality risk), while B3 and B4 point to possibly longevity-enabling processes (associations with age and mortality risk have opposite directions of effect).

Signature B3 included citric acid and trans-aconitic acid (aconitate) that were higher at older ages and EL, and were associated with a decreased mortality risk, thus suggesting an age-related protective/compensatory mechanism. This hypothesis is supported by other studies: citric acid increased during aging,33 and relatively higher levels of citric acid were associated with a younger biological age.34 Plasma levels of citric acid were significantly higher in centenarians when compared with non-centenarians,35 and dietary supplements of citric acid increased metabolic health and extended the lifespan in Drosophila melanogaster.36 Trans-Aconitic acid increased during aging for people in the age range of 40–65 years,37 but higher levels of this metabolite correlated with high mortality risk in both the Framingham Heart Study25 and Women’s Health Initiative Study.38 Both metabolites are part of the tricarboxylic acid cycle, an essential component of aerobic metabolism that occurs in mitochondria. The importance of the tricarboxylic acid cycle to longevity in lower organisms is well understood,39 and our data suggest that its activity might facilitate EL in humans.

A few signatures stand out as comprising potentially protective metabolites. Metabolites in signature D4 were elevated in EL, and higher levels predicted a decreased hazard for mortality, suggesting that these metabolites could be markers of longevity. Signature B3 included citric acid and trans-aconitic acid, which increased with older age and EL. Higher levels correlated with a decreased mortality risk, thus suggesting a protective role during old age. Citric acid levels increased by 0.3% for a year difference (Adj_p = 3.3E−13), were higher in EL compared to younger individuals (FC = 1.16, Adj_p = 2.7E−06), and a standard deviation increased from the mean in log-scale was associated with a 12% reduction of the HR for death (Adj_p = 0.0007). trans-Aconitic acid levels increased by 0.4% for a year difference (Adj_p = 5.3E−20), were higher in EL compared to younger individuals (FC = 1.26, Adj_p = 7.2E−12), and a standard deviation increase from the mean was associated with a 12% reduction of mortality risk (Adj_p = 0.00376).

They cite Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis 2021.

@John_Hemming

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#2

Going back through the references

Alternatively, greater concentrations of metabolites from carnitine and fatty acid metabolism (10-hydroxydecanoic acid, O-dodecanoyl-carnitine, tetradecenoyl carnitine, O-decanoyl-l-carnitine, acyl-C18:2-OH), TCA cycle (citrate), polyamine (putrescine), inositol (inositol 1-2-3-5-6-pentakisphosphate), sterol (pregna-4,9(11)-diene-3,20-dione), serine (phosphoserine), indole (indole-3-acetate), and ubiquinone (4-hydroxybenzoate) pathways were associated with a lower biological age.

The point about citrate is that it is a reasonably direct mechanism for the body to average out biological age as once in cells it feeds directly via ACLY into the acetyl-CoA pathway.

Accordingly, the serum discriminant model display in centenarians relatively lower amount of glycerophosphocholine (GPC), and higher amounts of N-acetlyglycoproteins (NAC), glutamine, citrate, creatinine, and phenylalanine.

Another interesting one, of course, is creatinine as higher levels generally indicate less well functioning kidneys, but also indicate more physical activity.

https://citrate.science/2024poster/poster.html

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#3

@John_Hemming for the win! But are there implications of wanting to not overdo it when young?

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#4

It depends what “it” is. Actually the priority is mitochondrial efficiency and it is always best to maintain that. Citrate is one of a number of tools that can prop up inefficient mitochondria.

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#5

What about this? Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice 2021

In the current work, we further explored the mechanisms involved in citrate-induced insulin resistance by supplementing regular chow with citrate to reach the amount of citrate found in common processed foods. Here, we show that an acute supplementation of citrate (24 hours) triggers several inflammatory and insulin-resistance-related markers in these animals. Furthermore, our data show that citrate supplementation impairs glucose tolerance test, insulin tolerance test and increases fasting insulinemia, supporting that alimentary citrate induces insulin resistance and dysmetabolism. Moreover, these metabolic effects of citrate are linked to the upregulation of lipogenic genes in the liver and hepatic inflammation as revealed by macrophage infiltration and polarization to the pro-inflammatory profile, altogether suggesting the induction and complication of nonalcoholic fatty liver disease (NAFLD) [14]. Thus, the current work gives light to evidence that this additive is not as harmless as the regulatory agencies and food industry believe

#6

Acute supplementation. Cue in bromide re: dose makes the poison. This article was previously linked and discussed and might shed light on the paradox though if I recall @John_Hemming disagreed with the mechanism the researchers impute to citrate:

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#7

This was John’s answer to the paper: Mitochondrial citrate metabolism and efflux regulate BeWo differentiation - #13 by John_Hemming

#8

@John_Hemming what do you make of this trans-aconitic acid? It’s completely unfamiliar to me and I see zero mentions on the forum either. Any hot takes?

#9

At the very first blush my guess would be that it serves as a surrogate for a functioning immune system which by the time you’re a centerian you probably lack, what with complete thymic involution. So the natural antibacterial properties must confer advantages but there’s probably a lot more to it than that.

#10

The cis isomer is part of the Krebs/Citric Acid/TCA cycle and is created from citric acid. AIUI the isomerisation can happen spontaneously.

I don’t know what the concentrations are. It could be simply a side effect of there being more citric acid.

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#11

But wouldn’t you expect the cis isomer to predominate if that’s all?

#12

Human Beings often have large doses of exogenous sodium citrate linked to either blood transfusion or dialysis. Hence we know where the limits are with citrate toxicity.

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#13

That’s right. Hadn’t thought of that. However there may be different considerations with acute supplementation (blood transfusions, other IVs) vs continuous long term moderate supplementation that can build up.

#14

That, however, can be converted to isocitrate whereas the trans isomer cannot (not via aconitase)

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#15

There are assumptions that the diet has perhaps 4g per day. There is a normal level in serum perhaps 50-100 microMolar. Normally the liver burns up citrate via SLC13A5, but some can enter other tissues.

People who have hepatic insufficiency can build up citrate to toxic levels. However, it is hard otherwise.

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