Abstract

Horvath’s epigenetic clock research has spotlighted a core set of 48 aging-related genes whose DNA methylation shifts closely track chronological age​. These genes – including key transcription factors, splicing regulators, and developmental genes – play pivotal roles in regulating metabolism, maintaining epigenetic patterns, and preserving cellular identity​. A unifying theme emerging from this work is the tight interplay between metabolic changes and epigenetic modifications during aging. For instance, older cells exhibit an imbalance in neurotransmitter metabolism: inhibitory GABA levels decline while excitatory glutamate accumulates, contributing to cellular stress and “dedifferentiation” of cell fate control​. At the same time, levels of α-ketoglutarate (αKG) – a crucial TCA-cycle metabolite required for DNA demethylation – become depleted with age (due to waning metabolic flux and GABA depletion), impairing the αKG-dependent demethylation of DNA and leading to aberrant hypermethylation and silencing of protective “youth” genes​. Compounding this metabolic-epigenetic shift, certain enzymes grow dysregulated with age: monoamine oxidase-B (MAO-B), a FAD-dependent enzyme, is upregulated in aging tissues and sequesters its FAD cofactor, while the NAD⁺-consuming enzyme CD38 is often overactivated, relentlessly hydrolyzing NAD⁺​ The combined effect is a drain of two essential mitochondrial cofactors – NAD⁺ and FAD – which starves mitochondria of energy substrates and hampers key repair enzymes, thereby exacerbating cellular aging and dysfunction​.Emerging evidence suggests that aging may be driven by such self-reinforcing metabolic and epigenetic disturbances, rather than by a one-way accumulation of random damage​. In this view, a decline in metabolites like αKG and NAD⁺ triggers epigenetic dysregulation, which in turn further impairs metabolism, creating a vicious cycle or feedback loop that propels aging forward. This perspective also highlights promising therapeutic interventions aimed at breaking the loop. For instance, restoring αKG levels (through supplementation) could rejuvenate DNA demethylation activity and prevent the silencing of youthful genes, while boosting NAD⁺ (via precursors or CD38 inhibitors) helps sustain sirtuin enzymes and mitochondrial function​. Likewise, inhibiting MAO-B could conserve FAD and mitigate oxidative byproducts, especially in the brain, thereby protecting mitochondrial efficiency​. By targeting multiple nodes of this network, such interventions – alone or in combination – aim to restore metabolic and epigenetic homeostasis in aged cells​ Taken together, these findings paint a picture of aging as an actively regulated biological program orchestrated by intertwined metabolic, epigenetic, and mitochondrial dysfunctions​.Rather than a passive wear-and-tear process, aging appears to be driven by a dynamic, maladaptive program – one that scientists may increasingly be able to modulate or even reset with multi-pronged therapies.

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How deeply rooted are the molecular drivers of aging, and what does their conservation across plants and animals reveal about longevity itself? Building on Horvath’s landmark epigenetic clock findings (Nature, August 2023), this comparative genomic study probes 49 pivotal genes in mammals, fish, reptiles, birds, insects, plants, bacteria, and archaea. Strikingly, only four of these genes—LARP1, SNX1, HDAC2, and PRC2—emerge as universal eukaryotic anchors, linking epigenetic and developmental processes from leaves to limbs. Beyond these plant-present regulators, additional tiers of conservation appear in insects—yet vanish in simpler prokaryotes—revealing a layered evolutionary tapestry of increasing regulatory sophistication. This cross-kingdom perspective offers potent insights for aging researchers and evolutionary biologists alike, suggesting that the very architecture of longevity is inscribed into genes that first took shape at life’s eukaryotic dawn.

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Abstract

Multiple lines of evidence suggest that high-dose vitamin D3 (cholecalciferol) can profoundly influence nuclear envelope integrity by modulating the expression and processing of lamin A—an essential nuclear scaffold protein that silences unneeded genes and maintains normal nuclear morphology. These effects are of particular interest in Hutchinson-Gilford progeria syndrome (HGPS), where a faulty lamin A (called progerin) drives accelerated aging, as well as in cancer cells that often downregulate lamin A to gain nuclear pliability. Recent in vitro work has shown that active vitamin D3 (1,25-dihydroxyvitamin D3 or calcitriol) reduces progerin production in HGPS cells while stabilizing critical DNA repair proteins such as BRCA1 and 53BP1, underscoring vitamin D’s broader role in genomic integrity. Furthermore, correcting lamin A deficits may force a shift from fermentative glycolysis (the Warburg effect) toward oxidative phosphorylation—supporting the metabolic theory that compromised mitochondrial function and a lax nuclear envelope go hand in hand in both cancer and progeria. This article also emphasizes the importance of supplementing vitamin K2 and magnesium when using high-dose vitamin D3 to avoid hypercalcemia.

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