The hallmarks of aging
The 2013 Lopez-Otin framework identified nine cellular and systemic hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. An updated 2023 review extends this to twelve. Useful anti-aging interventions target one or more hallmarks specifically. Peptides happen to have particularly tractable mechanisms against several: telomere attrition (Epitalon), GH-axis decline (Sermorelin/CJC-1295/Ipamorelin), NAD+ depletion (NAD+ replenishment), and mitochondrial dysfunction (MOTS-c).
Epitalon
Epitalon is a tetrapeptide (Ala-Glu-Asp-Gly) synthesized by Vladimir Khavinson at the St. Petersburg Institute of Bioregulation and Gerontology, as a synthetic analog of a pineal peptide. The Khavinson group's evidence base is the most extensive for any anti-aging peptide: a 15-year follow-up study reported significant reductions in mortality and accelerated-aging markers in elderly subjects given Epitalon over multiple seasonal courses (Korkushko et al., 2011, PMID: 21808782). The proposed mechanisms include telomerase activation in human somatic cells and restoration of pineal melatonin amplitude.
The evidence is striking but has limited independent replication outside the Khavinson group. Mechanism plausibility is strong; effect size in independent labs awaits demonstration. Standard protocol: 5–10 mg SC daily for 10–20 days, repeated 2–3 times yearly. Read the full Epitalon profile.
Sermorelin
Adult growth hormone secretion declines roughly 50% between ages 20 and 60. The mechanism is multifactorial: reduced GHRH amplitude from the hypothalamus, increased somatostatin tone, decreased pituitary GH stores. Sermorelin — a 29-amino-acid GHRH analog — restores GHRH signaling and gradually rebuilds endogenous GH pulse capacity. Unlike exogenous HGH, which suppresses endogenous secretion, Sermorelin works with the existing axis.
The GH-axis approach to aging targets visceral adiposity, sarcopenia, declining slow-wave sleep, and reduced subjective vitality — the cluster of complaints most strongly associated with adult GH deficiency. Typical protocol: 100–500 mcg SC at bedtime, fasted, daily for 8–12 week cycles. The combination CJC-1295 + Ipamorelin achieves more reliable GH pulse and is often substituted.
NAD+
NAD+ is the universal cofactor for the sirtuins (SIRT1–7), poly-ADP-ribose polymerases (PARPs), and CD38. All three classes consume NAD+ at increasing rates with age. By the seventh decade, tissue NAD+ levels are roughly half of young-adult baseline. Restoring NAD+ — via direct IV/SC infusion, or orally via precursors (NR, NMN) — improves mitochondrial function, DNA repair, and metabolic flexibility (Yoshino et al., Cell Metab, 2018, PMID: 29551589). Standard injection protocol: 100–500 mg IV or SC, weekly.
MOTS-c
The mitochondrial-derived peptide MOTS-c activates AMPK, restores insulin sensitivity, and reverses metabolic features of aging in mouse studies. It is one of the most mechanistically rigorous anti-aging peptides available. Standard: 5–10 mg SC, 2–3x weekly, 8–12 week cycles.
GHK-Cu
For dermal aging — fine lines, loss of dermal thickness, impaired wound healing — GHK-Cu has the strongest published evidence among peptide approaches (Pickart, 2008, PMID: 19021507). The copper-bound tripeptide acts as a growth-factor mimetic at the fibroblast level, increasing collagen synthesis, basement membrane integrity, and angiogenesis. Topical 1% formulations show clinical-grade improvements in wrinkles and skin elasticity over 12-week protocols.
Stacks
- Epitalon + Sermorelin (or CJC/Ipa) — circadian and GH-axis restoration together.
- NAD+ + MOTS-c — mitochondrial double-up.
- Epitalon + NAD+ — see our shop's Anti-Aging Stack.
- Full anti-aging — Epitalon + CJC/Ipa + NAD+ + MOTS-c rotated through annual cycles.
Protocols
Beginner (annual Epitalon course): Epitalon 10 mg SC daily for 20 days, run once in spring. Re-evaluate seasonal sleep, energy, and subjective vitality.
Intermediate (GH-axis + Epitalon): CJC-1295 100 mcg + Ipamorelin 200 mcg SC at bedtime 5 nights/week, 12 weeks. Concurrent Epitalon 10 mg SC daily for first 20 days. Re-evaluate IGF-1, body composition, sleep.
Advanced (full longevity stack): Quarterly cycles of Epitalon + CJC/Ipa + NAD+ + MOTS-c, with washout periods. Annual lab panel: CMP, lipid panel, A1c, fasting insulin, IGF-1, hsCRP, vitamin D, B12, ferritin.
Safety
Epitalon has no significant adverse events reported in the Khavinson literature; independent verification of long-term safety is limited. GH-axis peptides should not be used in active malignancy or uncontrolled diabetes. NAD+ infusion may cause transient flushing/chest tightness. MOTS-c is generally well-tolerated. GHK-Cu is safe topically; some people with copper sensitivity report irritation.
References
- Lopez-Otin C, Blasco MA, et al. The Hallmarks of Aging. Cell. 2013.
- Korkushko OV, Khavinson VKh, Shatilo VB, Antonyk-Sheglova IA. 15-year follow-up Epitalon study. Bull Exp Biol Med. 2011. PMID: 21808782.
- Yoshino J, Baur JA, Imai SI. NAD+ Intermediates. Cell Metab. 2018. PMID: 29551589.
- Lee C, Zeng J, et al. MOTS-c. Cell Metab. 2015. PMID: 25738459.
- Pickart L. The human tri-peptide GHK and tissue remodeling. Biochem Soc Trans. 2008. PMID: 19021507.