The longevity stack combines four mechanistically distinct anti-ageing compounds: epitalon (telomere/pineal), NAD+ (sirtuin/mitochondrial biogenesis), SS-31 (mitochondrial membrane antioxidant), and MOTS-c (mitochondrial-derived AMPK activator). Together they address telomere attrition, mitochondrial dysfunction, and deregulated nutrient sensing — three of the nine hallmarks of ageing.
18-month C57BL/6 mice. Establish baseline: body composition (EchoMRI), grip strength, rotarod, Y-maze (cognition), telomere length (qPCR), NAD+/NADH ratio (tissue), mitochondrial function (Seahorse), mtDNA copy number, 8-OHdG, IL-6/TNF-a.
2. 4-compound longevity intervention
Epitalon 0.1 mg/kg SC daily + NAD+ 500 mg/kg IP daily + SS-31 3 mg/kg SC daily + MOTS-c 5 mg/kg IP daily × 12 weeks in aged mice. vs individual compounds and vehicle control. Same endpoint panel as baseline at weeks 4, 8, 12.
3. Mechanistic arm — hallmark attribution
For each compound arm: measure primary mechanistic endpoint (epitalon → TERT/telomere, NAD+ → NAD+/NADH/sirtuin, SS-31 → cardiolipin/ETC, MOTS-c → AMPK/GLUT4). Establishes which hallmark each compound addresses most effectively.
4. Lifespan extension study (optional)
Epitalon + NAD+ full lifespan study in C57BL/6 from 18 months. Kaplan-Meier survival curves, tumour-free survival, body weight trajectory, cause of death pathology. Reproduces and extends Khavinson longevity model.
Why this combination?
The four compounds target distinct but interconnected ageing mechanisms. Epitalon activates hTERT — addressing telomere shortening, a primary driver of cellular senescence. NAD+ repletes the cofactor required for SIRT1/3 activity — restoring mitochondrial biogenesis (PGC-1a) and DNA repair capacity. SS-31 stabilises cardiolipin — the mitochondrial membrane phospholipid essential for ETC complex assembly and ROS prevention. MOTS-c activates AMPK/SIRT1 from a mitochondria-derived signalling peptide — restoring metabolic homeostasis independent of nuclear-encoded sirtuins. These four mechanisms are non-overlapping.
❓
Frequently Asked Questions
Why combine epitalon with NAD+ for longevity research?
Epitalon addresses telomere biology (hTERT/TERT pathway); NAD+ addresses the sirtuin/mitochondrial biogenesis axis. These are independent ageing pathways — combining them addresses two hallmarks simultaneously. In Khavinson et al. models, epitalon + thymalin (not NAD+) produced the greatest lifespan extension; the NAD+ + epitalon combination represents an evolution of this approach incorporating the sirtuin axis.
What does SS-31 add to a longevity stack that NAD+ does not cover?
NAD+ promotes mitochondrial biogenesis via SIRT1/PGC-1a — increasing mitochondrial number. SS-31 directly protects existing mitochondrial membranes by stabilising cardiolipin — improving ETC efficiency and reducing superoxide leak. SS-31 addresses mitochondrial quality; NAD+ addresses mitochondrial quantity. Both are needed for comprehensive mitochondrial longevity research.
What is the role of MOTS-c in this longevity stack?
MOTS-c is a mitochondria-derived peptide (encoded in mitochondrial 12S rRNA) that translocates to the nucleus under stress to activate AMPK and SIRT1-dependent gene expression. It is the only mitochondrially-encoded signalling peptide in the QSC catalog — making it uniquely relevant for studying the retrograde mitochondria-to-nucleus signalling axis of longevity.
