Gladyshev’s main points on age-related expansion of the small-molecule landscape
Where he said it What he said Why it matters eLife 2014 – Age- and diet-associated metabolome remodeling Long-term, untargeted LC-MS on >15 000 features in fly cohorts showed that “aging is associated with increased metabolite diversity and the appearance of many low-abundance compounds,” a trend that levelled off only in extreme old age. Gladyshev interprets the ever-growing tail of rare peaks as chemical “noise” created by damage and side-reactions; counting them is a quantitative read-out of cumulative molecular damage. Aging Cell 2016 – “rising deleteriome” review He defines the deleteriome as the totality of all age-related deleterious changes (mutations, epimutations, damaged metabolites, mis-folded proteins, etc.). Because the deleteriome is intrinsically heterogeneous, he argues the best biomarkers must capture “many diverse age-related parameters … for example, **genome-wide epigenetic changes, mutations, nontargeted metabolite profiling and gene expression.” Untargeted metabolomics is explicitly singled out as one of the few assays that can see the explosion of molecular species he predicts. J. Biol. Chem. 2017 – “Non-enzymatic molecular damage as a prototypic driver of aging” The paper explains that metabolic substrates possess “chemical potentialities far exceeding metabolic requirements”; the unused potential is realized spontaneously through Michael additions, Amadori rearrangements, Pictet–Spengler reactions, quinone polymerisation, carbamylation, etc., continually generating new small molecules and adducts that accumulate with age. This mechanistic work links the appearance of novel metabolites/adducts directly to unavoidable side-chemistry, making increased metabolite diversity a cause rather than a mere symptom of aging. Metabolomist podcast (“Aging Fluidity & Omics Signatures”, Jun 2024) Gladyshev reiterates that metabolomics gives a unique window on “fluid” age signatures that DNA methylation clocks cannot see, emphasising how small-molecule heterogeneity tracks rejuvenation in parabiosis, reprogramming and stress-recovery models. Shows he still sees untargeted metabolite/adduct profiling as central to next-generation aging clocks and intervention testing. Conceptual take-aways
- **Why metabolite/adduct diversity grows:**Metabolism is imperfect. Every enzyme’s substrate specificity leaks; non-enzymatic chemistry is relentless. Each leak or side-reaction creates a novel small molecule or a covalent adduct (the adductome). Because repair/clearance is never 100 %, the chemical state-space of an organism broadens over time.
- **Link to the adductome idea:**Gladyshev’s “deleteriome” explicitly includes the adductome—the constellation of covalent modifications on macromolecules produced by reactive metabolites and environmental electrophiles. His 2017 paper details how catecholamine quinones, thioester-derived acylations, Schiff-base cascades, etc., feed this pool.
- Biomarker implications:
- Metabolite-count curves (number of LC-MS features vs. age) can serve as a bulk deleteriome read-out; in flies they correlate with mortality deceleration late in life.
- Because many emergent species are ultra-low abundance, high-resolution, untargeted platforms (DIA-HRMS, pan-protein adductomics) are needed.
- Combining diversity metrics with canonical clocks (DNAm, proteomics) should improve biological-age estimation.
- **Intervention view:**Interventions that slow the creation of novel species (methionine restriction, lowered temperature, partial reprogramming) or accelerate their clearance (autophagy boosters, enhanced detox pathways) are, in Gladyshev’s framework, genuine anti-aging strategies.
In short: Gladyshev sees the ever-expanding catalogue of small molecules and adducts—not a single “dominant” lesion—as the molecular fingerprint of aging. Measuring that chemical diversification is, in his view, one of the most direct ways to gauge and eventually control the aging process.
https://academic.oup.com/exposome/article/4/1/osae001/7574628?login=false