The Dr. Who Unlocked the Secret of Aging—and Buried It in 1973

Max Odens was a man of many contradictions. On the one hand, he was a meticulous, detail‐obsessed Londoner who once nearly lost his standing at a local hospital after repeatedly writing letters to the press complaining about how filthy the city’s public telephone booths were. On the other, he was every bit a publicity seeker, forever angling for the next big headline. He was, at heart, a perfectionist with a penchant for stirring commotion. And lurking just beneath his showy exterior was a revolutionary scientist who, by a blend of serendipity and brilliance, stumbled upon what might have been the most earthshaking discovery in medical history: a way to prolong life dramatically, perhaps even “cure” aging.

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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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Posted in: D3

The Four Horsemen of Aging: How 4 Evolved Mammalian Aging Systems Reveal the Missing Half of Evolution

Abstract
A growing body of evidence challenges the conventional view that aging is merely an accidental byproduct of essential genes and metabolic processes. Instead, this paper revisits a long-overlooked 1998 hypothesis that posited aging is modular—composed of multiple, independently evolved systems that each co-opt the vulnerabilities of the last. Fresh insights are developed concerning short LARP1 (Horvath’s #1 pro-aging gene with an unusual RNA binding site on the protein) a scarcely studied nuclear lncRNA that likely truncates ATM and XP/CS mRNAs and downregulates/prevents the production of WRN by interfering with mRNA spliceosome functions. From these insights, how aging proceeds in at least four evolutionary waves is revealed. System #1 (plant-like vascular/structural decline) appears vestigial in humans, overshadowed/co-opted by Horvath’s universal epigenetic clock. System #2 centers on mitochondrial dysfunction in motile organisms. System #3, tied to advanced DNA repair and immune function, propels progeroid syndromes such as ataxia telangiectasia Cockayne syndrome, and xeroderma pigmentosum. Finally, system #4—emerging alongside sexual reproduction—dominates in Werner’s syndrome, unifying older pathways with newfound genomic instability.
In highlighting short LARP1’s proposed ability to sabotage crucial mRNA splicing leading to defective repair and structural proteins, a surprising synergy is illuminated: these sequentially-evolved senescence pathways act less like random breakdowns and more like a deliberate “orchestra” of aging. Each system is associated with one of the canonical Yamanaka factors (KLF4, Sox2, c-Myc, and Oct4), underscoring the developmental roots of senescence. Far from dismissing aging as a mere trade-off under antagonistic pleiotropy, new evidence is presented consistent with an evolutionarily conserved program—one that likely offers local species-level benefits in predator-rich ecosystems by preserving genetic and phenotypic diversity by preventing excessive, homogenizing contributions to the gene pool by single individuals. The same selection pressure also selects for menopause in humans and declining fertility in animals with aging. Interestingly, the same evolutionary logic that explains aging’s adaptive role applies to the advantage of sexual over asexual reproduction, as sexual reproduction further accelerates genetic (via recombination) and phenotypic diversity and bolsters resilience against evolving predators. For gerontologists, evolutionary theorists, and epigenetic researchers alike, this framework suggests that aging emerges from deeply adaptive, multi-layered processes rather than serendipitous decline, opening avenues for therapeutic disruption and a deeper understanding of life’s final act.

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Evolution’s Suicide Switch: MAO-B Forces a Rethink of Darwin’s Legacy

Abstract
Monoamine Oxidase A (MAO-A) and Monoamine Oxidase B (MAO-B) are flavin-dependent enzymes that progressively increase with age in many tissues. It is proposed that both serve as “death genes,” depleting Flavin Adenine Dinucleotide (FAD) and thereby reducing mitochondrial energy production—mirroring the known action of CD38, which depletes Nicotinamide Adenine Dinucleotide (NAD+). Although MAO-A retains certain developmental and sex-related roles, MAO-B appears to confer no clear early-life benefit and emerges as the first true, fully dedicated death gene documented. This discovery challenges classical evolutionary theories and suggests an unexpected “programming” of aging. The contrasting knockout phenotypes are detailed—dramatic aggression and neurotransmitter imbalance for MAO-A vs. subtle or minimal deficits for MAO-B. How the parallel depletion of NAD+ (by CD38) and FAD (by MAOs) undermines electron transport chain function in a near-symmetric manner is also examined. These findings open new therapeutic possibilities, including targeted inhibition of MAO-B (and MAO-A) and combined strategies preserving both NAD+ and FAD to mitigate age-related decline. This finding also calls into question a core principle of the selfish gene theory of evolution and suggests a need for a reevaluation of mainstream theory.

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NEW STUDY DISPROVES ALL MAINSTREAM THEORIES OF AGING-AND REVEALS THE NEW: PROGRAMMED LOSS OF CELLULAR DIFFERENTIATION THEORY OF AGING

Before we get started let me just whet your appetite about what is contained in the rest of this article. The results of the most important study on aging EVER, that will be the most important study of aging for all time- have just been released! Steve Horvath’s :

Universal DNA methylation age across mammalian tissues

The study proves conclusively that aging is selected for by evolution and is programmed. A result that contradicts all major mainstream theories of aging that have been proposed since the early 1900’s. It turns out August Weisman got the right answer in 1882 but with the wrong reasoning.

The new study also reveals the true cause of aging at the cellular level- the programmed loss of cellular differentiation.

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How to Save 90%+ On Any Supplement!

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