The LEV Foundation initiates RMR2, applying eight damage‐repair interventions to midlife mice with rapamycin baseline and exercise to assess lifespan and healthspan improvements.
Key points
RMR2 begins mid-life (18–20 months) in C57BL/6J mice with rapamycin baseline and voluntary exercise to assess rejuvenation capacity.
Eight interventions—including D-PUFAs, recombinant serum albumin, MSCs, partial reprogramming, IL-11 blockade, CASIN, LC-FACS inhibition, and oxytocin—target molecular and cellular aging mechanisms.
Twenty treatment combinations across male and female cohorts (50 mice each, 2000 total) evaluate lifespan, morbidity, and functional decline metrics.
Why it matters:
By testing combined molecular repair interventions in aged mice, RMR2 may reveal synergistic anti‐aging therapies to revolutionize longevity medicine.
Q&A
Why include rapamycin across all groups?
What are deuterated polyunsaturated fatty acids (D-PUFAs)?
How does partial cellular reprogramming rejuvenate tissues?
What is LC-FACS-based selective senolysis?
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Academy
Partial Cellular Reprogramming
Definition: Partial cellular reprogramming uses transient expression of key transcription factors—Oct4, Sox2, Klf4, and c-Myc, known collectively as the Yamanaka factors—to refresh cellular epigenetic patterns without fully reverting cells to pluripotency.
Mechanism: Aging cells accumulate DNA damage and epigenetic modifications that impair function. By temporarily activating the Yamanaka factors, cells partially erase age-associated epigenetic marks, restoring youthful gene expression profiles and improving DNA repair mechanisms. The process stops short of full de-differentiation, preserving the cell’s original identity while reversing aging hallmarks.
Delivery Methods:
- Viral vectors (e.g., lentivirus, AAV) to deliver transcription factor genes.
- Lipid nanoparticles carrying mRNA-encoded Yamanaka factors for transient expression.
- Chemical induction using small-molecule cocktails that activate endogenous reprogramming pathways.
Applications in Longevity Science: Preclinical studies demonstrate functional rejuvenation in key tissues—skin, muscle, liver, and neurons—leading to improved wound healing, increased regenerative capacity, and delayed onset of age-related diseases. Partial reprogramming holds promise for treating degenerative conditions like sarcopenia, neurodegeneration, and fibrosis.
Senolysis via LC-FACS Inhibition
Definition: Senolysis refers to the targeted elimination of senescent cells—cells that have lost the ability to divide and contribute to chronic inflammation and tissue dysfunction. LC-FACS inhibition specifically targets long-chain fatty acid–CoA synthetase.
Mechanism: Senescent cells exhibit disrupted lipid metabolism, with elevated levels of lysophosphatidylcholine (lysoPC) and free arachidonic acid. LC-FACS inhibition blocks the activation of free fatty acids into their CoA derivatives, impairing membrane lipid repair and energy metabolism. This selective vulnerability induces ferroptosis-like cell death in senescent populations while sparing healthy cells with intact lipid homeostasis.
Significance for Longevity: Clearing senescent cells reduces chronic inflammation (inflammaging), improves tissue function, and extends healthspan in animal models. LC-FACS–based approaches offer a novel, metabolism-centric senolytic strategy with potential for high specificity and minimal off-target effects, representing a next-generation anti-aging therapy.