Aging & Longevity

Systemic MOTS-c injection restored peptide levels in aged mice and successfully reversed age-related skeletal muscle insulin resistance.

Plasma MOTS-c levels decline with age in both mice and humans. Circulating levels are significantly lower in obese individuals and type 2 diabetes patients.

Humanin overexpression in C. elegans increased lifespan in a daf-16/Foxo-dependent manner. Levels remain stable in long-lived naked mole-rats and are elevated in centenarian offspring.

Twice-weekly treatment with humanin analog HNG improved metabolic healthspan parameters and reduced inflammatory markers in middle-aged mice.

Multiple small human trials demonstrate that NAD+ precursors (NR, NMN) reliably raise blood and tissue NAD+ levels. In a pharmacokinetic study of 12 healthy subjects, single-dose oral NR produced up to 2.7-fold increases in blood NAD+ (Trammell et al., 2016). Similar NAD+ elevations were confirmed in aged skeletal muscle (Elhassan et al., 2019) and in the brains of Parkinson's patients (Brakedal et al., 2022). Note: direct oral NAD+ has poor bioavailability; most evidence uses precursors NR or NMN.

Reduced inflammatory markers were observed across multiple human and animal studies. In aged men, NR reduced circulating inflammatory cytokines (Elhassan et al., 2019). In Parkinson's patients, NR lowered inflammatory markers in serum and CSF (Brakedal et al., 2022). NAD+ metabolism modulates immune response, T cell function, and inflammaging pathways (Navarro et al., 2022). Evidence is consistent but from small, heterogeneous studies.

A double-blind, placebo-controlled crossover RCT in 12 aged men showed that 1g daily NR for 21 days augmented the skeletal muscle NAD+ metabolome and induced transcriptomic anti-inflammatory signatures, with reduced circulating inflammatory cytokines (Elhassan et al., 2019). In prediabetic women, NMN also upregulated muscle remodeling genes (Yoshino et al., 2021). Evidence limited to two small trials.

Moderate increase in telomerase activation

Small increase in telomere length observed

Moderate reduction in senescence markers

Small improvement in frailty measures

Changes in apolipoprotein and immunoglobulin levels

A 2025 study in C. elegans found that maral root extract extended both lifespan and healthspan in nematodes, with 20-hydroxyecdysone (ecdysterone) identified as the primary bioactive compound. This is a very preliminary invertebrate model with no mammalian or human replication.

In C. elegans, 8mM oxaloacetate supplementation extended lifespan by approximately 25% via an AMPK/FOXO(DAF-16)-dependent pathway, mimicking caloric restriction effects (Williams et al. 2009). This pathway is independent of Sir-2.1. No mammalian lifespan studies have been conducted; human longevity effects remain entirely speculative.