Longevity & Mitochondrial

Humanin is a 24-amino acid mitochondrial-derived peptide (MDP) encoded by a small open reading frame within the mitochondrial 16S ribosomal RNA gene (MT-RNR2). First discovered in 2001 as a neuroprotective factor, humanin belongs to the novel class of mitochondria-derived peptides and represents the first peptide identified to be encoded by mitochondrial DNA. The peptide can be translated both in the mitochondrial matrix (producing a 21-amino acid variant) and the cytosol (producing the full 24-amino acid peptide), with both forms being biologically active. Humanin functions as a signaling molecule with cytoprotective and antiapoptotic properties, exerting beneficial effects across multiple organ systems including the brain, heart, skeletal muscle, and vascular tissues. Research has demonstrated humanin's role as a regulator of both lifespan and healthspan, with levels naturally declining with age and in various disease states including Alzheimer's disease, diabetes, and cardiovascular disorders. The peptide exerts its effects through multiple mechanisms including binding to cell surface receptors (FPRL1/2 and trimeric CNTFR-α/gp130/WSX-1 complex), intracellular protein interactions (BAX, IGFBP3), and modulation of key signaling pathways (STAT3, AMPK, ERK1/2). The highly potent S14G-humanin analog (HNG) shows 1000-fold greater biological activity than native humanin. While extensive preclinical evidence supports humanin's therapeutic potential for age-related diseases, neurodegenerative disorders, metabolic dysfunction, and cardiovascular conditions, the peptide remains investigational with no completed human clinical trials for therapeutic applications. Humanin is not approved by the FDA or other regulatory agencies for clinical use.

CJC-1295 with DAC is a synthetic analog of growth hormone-releasing hormone (GHRH) developed by ConjuChem Biotechnologies, featuring a Drug Affinity Complex that binds to serum albumin for extended half-life of 6-8 days. Clinical trials demonstrated sustained increases in growth hormone (2-10 fold) for 6+ days and IGF-1 (1.5-3 fold) for 9-11 days after a single injection. The peptide was investigated in Phase 2 trials for HIV-associated lipodystrophy but was discontinued following a participant death, though it showed safety and tolerability in healthy adults at doses of 30-60 μg/kg.

Epitalon (also known as Epithalon or Epithalone) is a synthetic tetrapeptide with the amino acid sequence Ala-Glu-Asp-Gly (AEDG), originally derived from epithalamin, a bovine pineal gland extract. Its primary mechanism of action involves activation of telomerase enzyme activity, leading to telomere elongation in human somatic cells, as well as regulation of melatonin production and circadian rhythms. Over 25 years of research has demonstrated geroprotective effects in multiple animal models, including increased lifespan (11-16% in fruit flies, 12-13% maximum lifespan extension in mice), improved biomarkers of aging, and inhibition of spontaneous tumor development. Limited human clinical trials have shown positive results in treating retinitis pigmentosa and reducing cardiovascular mortality in elderly patients with coronary disease. However, Epitalon remains an experimental research compound with no FDA or EMA approval for therapeutic use. Its regulatory status is that of an investigational peptide, not approved for clinical application in the United States or Europe, though it has been extensively studied in Russian research institutions for decades.

Ipamorelin is a synthetic pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH₂) functioning as a selective growth hormone secretagogue that binds to ghrelin receptors (GHS-R1a) in the anterior pituitary to stimulate growth hormone release. Originally developed by Novo Nordisk, it represents the first GHRP-receptor agonist with selectivity for GH release comparable to GHRH, notably without stimulating cortisol or ACTH secretion even at doses 200-fold above therapeutic levels. While investigated in Phase II clinical trials for postoperative ileus (discontinued due to lack of efficacy), ipamorelin demonstrates promising preclinical effects on bone growth, muscle preservation, and metabolic function. Currently, it lacks FDA approval for any indication and exists in a regulatory gray area where it's marketed as a research chemical but widely used off-label in peptide therapy clinics for anti-aging, body composition optimization, and recovery enhancement, while simultaneously being prohibited by WADA as a performance-enhancing substance in competitive sports.

Thymalin is a polypeptide complex extracted from calf thymus tissue, developed by Prof. Vladimir Khavinson in the 1970s as an immunomodulatory bioregulator. It contains short peptides (KE, EW, EDP) that epigenetically regulate gene expression, stimulate hematopoietic stem cell differentiation into T-lymphocytes, and modulate inflammatory pathways. Extensive clinical research in Russia demonstrates geroprotective effects, with 2-4 fold mortality reduction in elderly populations and efficacy in treating immune dysfunction, viral infections, cancer support, and COVID-19.

Pinealon (EDR) is a synthetic tripeptide bioregulator composed of glutamic acid, aspartic acid, and arginine (Glu-Asp-Arg) developed by Russian scientist Vladimir Khavinson. Originally isolated from the polypeptide neuroprotective drug Cortexin, it demonstrates potent neuroprotective properties through multiple mechanisms including ROS suppression, gene expression regulation, and epigenetic modulation. Pinealon has been extensively studied in Russian scientific literature for its effects on cognitive function, neuroplasticity, and cellular aging processes.

GHK-Cu (glycyl-L-histidyl-L-lysine-copper) is a naturally occurring copper-binding tripeptide first isolated from human plasma in 1973. It functions as a signaling molecule that modulates multiple cellular pathways involved in tissue repair and regeneration. The peptide's concentration in human plasma declines from approximately 200 ng/mL at age 20 to 80 ng/mL by age 60, correlating with decreased regenerative capacity. GHK-Cu works through several mechanisms including copper ion transport, gene expression modulation (affecting over 4,000 human genes), collagen and elastin synthesis stimulation, antioxidant activity via superoxide dismutase enhancement, and growth factor pathway activation. Research demonstrates efficacy in wound healing, skin regeneration, hair follicle stimulation, and anti-inflammatory responses across multiple tissue types. The peptide is not FDA-approved for therapeutic use but is widely used in cosmetic products. It was recently added to FDA's Category 1 bulk substances list for 503A compounding, though not for injectable routes. GHK-Cu is available primarily through compounding pharmacies for research purposes and in topical cosmetic formulations marketed for anti-aging and skin rejuvenation applications.

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) is a 16-amino-acid peptide encoded within the mitochondrial genome's 12S ribosomal RNA region, discovered in 2015 by researchers at the University of Southern California. This mitochondrial-derived peptide functions as a signaling molecule that translocates to the cell nucleus during metabolic stress, where it regulates nuclear gene expression through AMPK-dependent mechanisms. Primary research has focused on its roles in metabolic regulation, exercise performance, aging, insulin resistance, obesity, cardiovascular health, and bone metabolism. MOTS-c levels naturally decline with age in plasma, though skeletal muscle expression may increase compensatorily. The peptide is not approved by the FDA or other regulatory agencies for clinical use and remains an investigational compound available only in research settings. It is prohibited by the World Anti-Doping Agency (WADA) under metabolic modulators. Currently, MOTS-c is only available through research suppliers and is not approved for human therapeutic use outside of clinical trials.

Endoluten is a peptide bioregulator complex derived from pineal gland tissue, developed by Professor Vladimir Khavinson at the St. Petersburg Institute of Bioregulation and Gerontology. It contains short peptides (molecular weight <5000 Da) including the tetrapeptide AEDG (Ala-Glu-Asp-Gly), which regulates melatonin synthesis, circadian rhythms, and neuroendocrine function. Clinical and experimental studies demonstrate geroprotective effects including normalized hormonal function, improved cardiovascular and immune parameters, and significant mortality reduction in elderly populations over 6-8 year follow-up periods.

FOX-04-DRI (Proxofim) is a synthetic 46-amino acid cell-penetrating peptide composed of D-amino acids (D-retro-inverso configuration) designed to selectively eliminate senescent cells by disrupting the FOXO4-p53 protein interaction. By perturbing this critical survival mechanism, the peptide causes p53 nuclear exclusion and triggers selective apoptosis specifically in senescent cells while sparing healthy cells, demonstrating an 11.73-fold selectivity difference. Preclinical studies in aged and accelerated-aging mouse models have shown restoration of tissue homeostasis, improved renal and mitochondrial function, fur density restoration, enhanced physical fitness, and neutralization of chemotherapy-induced toxicity, positioning it as a promising senolytic agent for age-related diseases and healthspan extension.

Glutathione (GSH) is a tripeptide composed of glutamate, cysteine, and glycine that serves as the body's most abundant endogenous antioxidant and critical regulator of oxidative stress, redox homeostasis, and immune function. It functions through direct neutralization of free radicals and as a cofactor for antioxidant enzymes like glutathione peroxidase. Research applications span neurodegenerative diseases (Alzheimer's, Parkinson's), metabolic disorders (diabetes, NAFLD), respiratory conditions (COPD), immune function (COVID-19), exercise performance, and dermatological applications. Clinical trials demonstrate that oral supplementation (250-1000 mg daily) can increase tissue glutathione levels by 17-35% in blood compartments and up to 260% in buccal cells, with evidence showing improvements in oxidative stress markers, glycemic control in diabetics, liver function in NAFLD, and reduced muscle fatigue. Glutathione is not FDA-approved as a drug but is available as a dietary supplement; intravenous formulations lack FDA approval for cosmetic uses and carry safety concerns. The compound is widely researched with generally favorable safety profiles for oral and topical administration.

CJC-1295 no DAC, also known as Modified GRF 1-29, is a synthetic analog of growth hormone-releasing hormone (GHRH) consisting of 29 amino acids with four strategic amino acid substitutions designed to enhance stability and bioactivity. Unlike CJC-1295 with DAC, this variant lacks the drug affinity complex, resulting in a shorter half-life of 30 minutes to 2 hours that promotes pulsatile growth hormone secretion mimicking natural physiological patterns. Research demonstrates it can increase growth hormone levels by 2- to 10-fold and IGF-1 concentrations by 1.5- to 3-fold in clinical trials. The peptide has been studied for potential applications in age-related GH decline, body composition optimization, and metabolic health. CJC-1295 no DAC is not FDA-approved for human use and is classified as a prohibited substance by WADA for athletic competition. It is available through compounding pharmacies for research purposes, though regulatory status remains uncertain following recent FDA actions on peptide compounding.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme found in all living cells, first discovered by British biochemist Arthur Harden and colleagues in 1906 while studying fermentation. NAD+ functions as a critical electron carrier in cellular metabolism and serves as a substrate for enzymes including sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38. Its primary mechanisms involve facilitating redox reactions in energy metabolism, regulating mitochondrial function, supporting DNA repair processes, and modulating cellular signaling pathways. Research areas include aging and longevity, metabolic disorders, cardiovascular health, neurodegenerative diseases, and mitochondrial dysfunction. NAD+ levels naturally decline with age, prompting investigation of supplementation with precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). While NAD+ itself is not FDA-approved as a drug, precursors such as NR have received Generally Recognized as Safe (GRAS) status and are commercially available as dietary supplements.

Small Humanin-Like Peptides (SHLPs 1-6) are a family of mitochondrial-derived peptides encoded by the 16S ribosomal RNA region of mitochondrial DNA, each comprising 24-38 amino acids. These microproteins function as age-dependent regulators of cellular metabolism, apoptosis, insulin sensitivity, and inflammatory responses. SHLP2 and SHLP3 exhibit cytoprotective effects by enhancing mitochondrial function and reducing oxidative stress, while SHLP6 demonstrates opposing pro-apoptotic activity. Emerging research indicates these peptides play crucial roles in metabolic disorders, neurodegenerative diseases, and aging-related pathologies, with SHLP2 showing particular promise as a therapeutic target for obesity, diabetes, macular degeneration, and Parkinson's disease.

MK-677 (ibutamoren) is a non-peptide, orally-active growth hormone secretagogue that selectively mimics the action of ghrelin, stimulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1) secretion. Originally developed by Merck Research Laboratories, it increases GH secretion by up to 97% through activation of the ghrelin receptor, producing sustained elevations in IGF-1 levels comparable to those seen in younger adults. Clinical research has explored its potential applications in muscle wasting, osteoporosis, growth hormone deficiency, frailty, and age-related decline. While studies have demonstrated increases in lean body mass, bone turnover markers, and improved sleep quality, MK-677 remains an investigational drug without FDA approval. Safety concerns include increased risk of congestive heart failure in elderly populations, impaired insulin sensitivity, elevated fasting glucose levels, and fluid retention. It is currently banned by the World Anti-Doping Agency and listed as a prohibited dietary supplement ingredient by the U.S. Department of Defense due to its growth hormone-releasing properties and potential health risks.