Primordial Pathways of Aging: The Four Plant-Animal Genes That Shaped Eukaryotic Longevity

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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Posted in: D3

High-Dose Vitamin D3, Mitochondrial Bioenergetics, and the Metabolic Theory of Cancer: A Potential for Prevention and Reversal

Abstract

Recent anecdotal evidence and clinical observations suggest that high-dose vitamin D3 (cholecalciferol) supplementation may have an underappreciated anti-cancer effect. Concurrently, the metabolic theory of cancer, espoused by Thomas Seyfried and others, highlights the importance of mitochondrial bioenergetics and the Warburg effect in oncogenesis. This article synthesizes these perspectives, proposing that high-dose vitamin D3 can enhance mitochondrial function and provide the energetic “push” needed to carry out proper apoptosis—a process that can stall under conditions of metabolic insufficiency. We further explore how classic oncogenic mutations (e.g., TP53, RB1, PTEN, BCL-2 family genes) compromise apoptosis in ways that are exacerbated by impaired mitochondrial energy output. Drawing from case reports, mechanistic studies on vitamin D3 and histone deacetylases (particularly HDAC2), and the evolutionary logic that cancer may be a reversion to a more primordial cell state, we present a compelling case for high-dose vitamin D3 as an adjunctive or primary therapy that targets the metabolic underpinnings of malignancies.

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The 48 Genes that Shape Aging: A Deep Exploration of Horvath’s Universal Mammalian Aging System

I had AI do a quick summary of a very comprehensive deep dive study of Horvath’s 48 aging related genes from the first preprint  of his seminal paper Universal DNA methylation age across mammalian tissues -Nature Aging August 2023- The deep dive will be available in my upcoming book on the subject
here’s what  it gave us:

What follows is an overview of Stephen Horvath’s Universal Mammalian Epigenetic Aging system. This updated review:

Clarifies that Thymine DNA Glycosylase (TDG), not TET enzymes, is the primary mechanism preventing hypermethylation of these aging-related genes (TDG is α-ketoglutarate dependent).
Explains that the initial 48 genes come from Horvath’s first preprint, and subsequent revisions have added or changed several genes (including transcription factor SP1).
Highlights how SP1 ties together MAO-A/MAO-B, FAD sequestration, WRN protein expression, and a potential impact on aging processes.
Presents a CD38/NAD+ analysis of the 48 genes, discussing how some of them may influence CD38 activity, thereby modulating NAD+ levels.

Throughout, we underscore the interplay of GABA–α-KG–glutamate, the overrepresentation of splicing-related genes, and the newly emphasized roles of SP1 and MAO in driving epigenetic and metabolic shifts that contribute to aging.

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