Metabolomics thread

[InquilineKea]

Lower choline is associated with more efficient fiber structure (same with higher NAA levels) [at least in ONE study]. I mean it shows that ageotypes are unique to specific people (you need spatial metabolomics) otherwise an elevation in one metabolite could mean many different things [it could mean higher turnover *or* higher degradation *or* inefficient turnover]

https://www.rapamycin.news/t/analysis-of-the-metabolomic-state-informs-on-metabolite-profiles-associated-with-disease-risk/5142

DMTPA, vanillylmandelic acid, PFAS increase aging

L-serine decreases aging

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796397/ (methionine-sulfoxide...)

Edited August 14, 2023 by InquilineKea

[InquilineKea]

https://www.rapamycin.news/t/analysis-of-the-metabolomic-state-informs-on-metabolite-profiles-associated-with-disease-risk/5142

https://link.springer.com/article/10.1007/s11357-023-00827-0?fbclid=IwAR0M4Zn8fy5cU4BAl__phs_lzxmpRikdu1kvBDrY6wzHpMqZ7a8z6Dz05c0

 

Edited July 11, 2023 by InquilineKea

[InquilineKea]

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Our work implicates the TCA cycle in human healthy aging. While discrepancies in the field exist [32], a vast body of literature also implicates abundance of TCA cycle metabolites in longevity, in line with our findings. For example, supplementation of the TCA cycle components malate and fumarate activate nuclear translocation of the FOXO/DAF-16 longevity gene, increase oxidative stress resistance, and extend lifespan in C. elegans worms [33]. Supplementation of TCA cycle component oxaloacetate also extends lifespan in worms dependent on the longevity gene FOXO/DAF-16 [34]. Supplementation of succinate, citrate, and alpha-ketoglutarate also extend lifespan in worms [35]. Furthermore, supplementation of citrate reduces energy status and extends lifespan in Drosophila melanogaster flies, and in mice fed a high-fat diet citrate improves metabolic health and memory [36]. Adding to this, TCA cycle genes are upregulated in Ames dwarf mice and little mice, which are both long-lived strains [37]. Functionality of the TCA cycle is also preserved when comparing long-lived to short-lived strains of Brown-Norway rats [38]. Remarkably, the TCA cycle intermediate alpha-ketoglutarate alone fed to mice extends lifespan and compresses morbidity [39]. In humans, a retrospective study using DNA methylation clocks to assess biological age found that supplementing alpha-ketoglutarate and certain other vitamins conferred an average of 8 years reduced biological age after an average of 7 months of use [40].

The finding that the TCA cycle was so strongly associated to decelerated aging in our data opens more questions. Firstly, it may be possible that beta-oxidation is feeding the TCA cycle. This is in line with observations that higher beta-oxidation is also present in long-lived mice [41]. Interestingly, our previous work in aging mice has suggested a shift in fat metabolism with aging [42]. However, dedicated metabolic flux experiments would be required to address this, which is difficult to perform in humans. Secondly, it may be that our measures on the TCA cycle in blood plasma serve as an indirect readout of mitochondrial activity in tissues. Indeed, our previous work with the same cohort used in PhysiAge validations implicated increased mitochondrial mass in the trained older adults [16, 25]. Again here, dedicated flux experiments would be required to trace whether muscle TCA cycle metabolism contributes to blood plasma TCA cycle components. Of additional consideration, it may be possible that the nature of metabolomics, being targeted, has had our investigational lens focus on known pathways including the TCA cycle. It would be of interest to perform these analyses using untargeted metabolomics. Of final note, our own study implicating the TCA cycle involved trained older adults, and therefore increasing TCA cycle constituents may in the end be best achieved simply by training more, rather than by supplementation strategies. In conclusion, these and our own findings support two main conclusions: (1) the function of the TCA cycle is causally linked to healthy aging across species, also in humans; and (2) an aging score derived from physiological parameters can serve as a proxy for individuals to assess their own biological aging.

 

 

[InquilineKea]

https://www.nature.com/articles/s41551-022-00999-8

Lustgarten got 500 metabolites from this. Iollo

Edited June 10, 2023 by InquilineKea

[Mike Lustgarten]

Any luck with them sending you the list?

[InquilineKea]

Yeah I got them now.. Some of the stuff on the ION panel isn't there, but they're planning to include more, so I don't feel like I need to rush an ION panel now

Edited June 11, 2023 by InquilineKea

[InquilineKea]

[deleted text]

Edited September 16, 2023 by InquilineKea

[InquilineKea]

https://diabetesjournals.org/care/article/45/4/1013/144892/Metabolomics-and-Type-2-Diabetes-Risk-An-Updated

I'm elevated in

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Higher levels of short-chain acylcarnitines C4-DC (RR_1-SD 1.10 [1.02–1.18], I² = 0%, τ² = 0.000, n = 4), C4-OH (RR_1-SD 1.09 [1.02–1.16], I² = 0%, τ² = 0.000, n = 6), C5 (RR_1-SD 1.13 [1.08–1.18], I² = 18%, τ² = 0.001, n = 14), and C5-OH (RR_1-SD 1.14 [1.03–1.26], I² = 58%, τ² = 0.008, n = 6) were associated with higher type 2 diabetes risk

https://hmdb.ca/metabolites/HMDB0013127

But there's very little other info on it The specifics don't seem to matter much

https://pharmrev.aspetjournals.org/content/74/3/506.long#sec-3

there's an outside chance it could be to excess butryate from very high fiber consumption, but I'll have to look more up into this

Quote

Short-chain hydroxyl acylcarnitines (e.g., 3-hydroxybutyrylcarnitine) can be formed from 3-hydroxybutyryl-CoA (Soeters et al., 2012). 3-Hydroxybutyrylcarnitine has been associated with fasting and ketosis but also with insulin resistance and type 2 diabetes (Soeters et al., 2012).

 

Edited July 11, 2023 by InquilineKea

[InquilineKea]

https://www.rapamycin.news/t/age-prediction-from-human-blood-plasma-using-proteomic-and-small-rna-data-a-comparative-analysis/8264

[InquilineKea]

 

[InquilineKea]

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We investigated 14 complex lipid classes, covering 964 molecular species and 267 fatty acid composites, with biological aging. We found complex lipid species to be differently associated with different rates of biological aging. Higher levels of molecular species belonging to the neutral lipids (MAG, DAG, TAG), phospholipids (PE, PE(O), PE(P)), and sphingolipids (CER, DCER) classes were associated with accelerated biological aging, whereas higher levels of distinct other molecular species (i.e., LPC, HCER, and LCER) were associated with slower biological aging. CE, PC, and LPE molecular species with odd-numbered (i.e., 15 and 17) fatty acid tail lengths were associated with slower biological aging, yet even-numbered fatty acid tail lengths were associated with faster biological aging. Importantly, in silico pathway analysis revealed that lipids that were associated with biological aging estimators were mainly involved in known longevity and aging-related pathways, revealing their role as potential determinants of biological aging across the lifespan in the general population.

Very little work has explicitly assessed the value of LPC species as potential human blood-derived biomarkers of human aging. Circulating LPCs are generated by phospholipases A2 from the PC. The most abundant LPC in human plasma is 16:0, followed by 18:2, 18:0, 18:1, 20:4, and other minor species. Here we found that higher levels of 13 out of 19 LPC species exhibit a robust association with slower biological aging, suggesting that LPC species may contribute to healthy aging. Our findings expand on those from recent epidemiological studies, which assessed a limited number of LPC species, and reported low concentrations of certain circulating LPCs (i.e., 18:2 and/or 17:0) to be associated with several aging-related phenotypes and disorders, including memory impairment, gait speed decline, and incident myocardial infarction. Moreover, elevated LPC (18:1) levels have been reported in centenarians. Potential biological mechanisms through which LPCs could contribute to slower biological aging and less age-associated functional decline are anti-oxidative stress and anti-inflammatory responses.

The major phospholipids in eukaryotic biomembranes are phosphatidylcholine (PC), and phosphatidylethanolamine (PE), which were also quantified in our study. PC can be synthesized by a three-step methylation of PE. We found that higher levels of various PE species were related to accelerated biological aging across the lifespan, whereas higher levels of polyunsaturated PCs were associated with slower biological aging. Higher levels of species with fewer double bonds tended to be associated with accelerated biological aging. These findings are in line with previous studies that found associations between higher levels of saturated and monounsaturated PCs and increased risk of cardiovascular diseases and type 2 diabetes. Conversely, polyunsaturated PC species have been linked to longevity, which might be due to their antioxidative and cardioprotective properties. PE species, the second most abundant membrane phospholipids, have been identified as modulators of inflammation and apoptosis, yet little is known about the properties of specific PE species.

Higher TAG levels are linked to an increased risk of cardiovascular diseases and Alzheimer's disease. Small-scale lipidomic profiling in longevity studies also found lower levels of TAG species (including TAG 46:5, 47:5, 52:1, 54:7, 54:6, 56:6, 56:7, 57:2) to be associated with healthy aging. Our findings extend these previous reports by showing that 361 out of 519 TAG species across different chain lengths and double bonds were associated with accelerated biological aging. Few studies have investigated the association between other neutral lipids (including CE, MAG, and DAG) and longevity or healthy aging. We found that higher levels of DAG species or lower levels of CE species were related to an accelerated rate of biological aging, indicating that almost all neutral lipids could potentially influence longevity.

 

Very cool! One of the top hits that changed in CSF with aging in our dataset was a phospholipase (Lp-PLA2). Congrats Andy!

Edited September 3, 2023 by InquilineKea

[InquilineKea]

If metformin increases ether lipids...

 

 

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Higher plasmalogen levels in naked mole-rat tissues versus mice are speculated to contribute to protection of cellular membranes via a reduction of oxidative stress (Mitchell et al., 2007). Similarly, exceptionally long-lived humans harbor higher levels of phosphatidylcholine-derived, short chained alkyl ether lipids and a lower levels of phosphatidylethanolamine-derived longer chained plasmalogens (Pradas et al., 2019), but these associations are of unclear functional significance. Although it is clear that ether lipid deficiency in C. elegans prevents longevity downstream of mitochondrial electron transport chain dysfunction, mTOR deficiency, caloric restriction, and biguanides alike, the precise lipid(s) conferring this activity remains unknown. Each of these longevity paradigms have features of nutrient deficiency, energy stress, or nutrient sensing, so it is possible that ether lipids are at least part of the common effector arm conferring benefit in aging to various forms of metabolic stress.

Our results suggest that unsaturated fatty acids and phosphatidylethanolamine ether lipids are essential to the health promoting effects of biguanides. Although we see major shifts in abundance of alkenyl ether lipids, genetic evidence of necessity of ether lipids, and requirement for the synthesis of mono- and poly-unsaturated fatty acids in biguanide-induced longevity, determination of the specific lipids necessary for promoting healthy aging awaits the ability to modulate the level of specific ether lipids. Additionally, disruption of ether lipid biosynthesis has been shown to increase the proportion of stearate (18:0) and other saturated fatty acids (Shi et al., 2016). Thus, at this time, we cannot rule out the possibility that biguanide-stimulated alterations in ether lipid biosynthesis serves to divert accumulation of lipid species that are detrimental to lifespan, for instance, saturated fatty acids. Nonetheless, in light of our finding that ether lipids prompt metabolic stress defenses, this alternative mechanism is less likely. Definitive proof will require a deeper understanding of the regulation of specific steps dictating the synthesis and modification of ether lipids of different fatty alcohol and fatty acid composition.

Based upon our findings, ether lipid synthesis is likely to be regulated post-translationally by biguanide treatment. The demonstrated increase in plasmalogens and specific ether lipids are both consistent with increases in activity of the ether lipid biosynthetic machinery.

 

 

[InquilineKea]

https://www.nature.com/articles/s41467-023-41515-z