Condition
Aging & Longevity
Aging is the gradual decline in how well the body's cells make energy and repair themselves. The evidence is moderate for two peptides: humanin extended lifespan in worms, and its levels were higher in the children of centenarians, while MOTS-c eased age-related muscle insulin resistance in older mice. Nearly all of this is animal or lab work, so it says little yet about people.
Sources: PMID 32575074; PMID 25738459
- Updated
- How we grade
- 100 studies cited
- Supplements studied
- 4
- Medicines and peptides
- 4
- Graded outcomes
- 14
Evidence by supplement
- Strong
- Moderate
- Limited
- Very limited
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Cellular NAD+ Levels 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. | Improves (the measure goes up) | Moderate effect | 7 studies | 84 people | ||
Studies that measured cellular nad+ levels
| ||||||
| Systemic Inflammation 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. | Improves (the measure goes down) | Small effect | 5 studies | 72 people | ||
Studies that measured systemic inflammation
| ||||||
| Skeletal Muscle NAD+ Metabolome and Anti-inflammatory Markers 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. | Changes; see studies | Small effect | 2 studies | 37 people | ||
Studies that measured skeletal muscle nad+ metabolome and anti-inflammatory markers | ||||||
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Senescent Cell Markers Moderate reduction in senescence markers | Improves (the measure goes down) | Moderate effect | 75 people | |||
| Physical Function in Elderly Small improvement in frailty measures | Improves (the measure goes up) | Small effect | 40 people |
Oxaloacetate
- Lifespan Extension: improves
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Lifespan Extension 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. | Improves (the measure goes up) | Moderate effect | 2 studies | |||
Maral root
- Longevity: improves
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Longevity 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. | Improves (the measure goes up) | Small effect | 1 study | |||
Studies that measured longevity | ||||||
Prescription medicines and peptides studied, for context
MOTS-c
- Age-Related Insulin Resistance: improves
- MOTS-c Plasma Levels: improves
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Age-Related Insulin Resistance Systemic MOTS-c injection restored peptide levels in aged mice and successfully reversed age-related skeletal muscle insulin resistance. | Improves (the measure goes down) | Moderate effect | 11 studies | |||
| MOTS-c Plasma Levels 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. | Improves (the measure goes down) | Moderate effect | 3 studies |
Humanin
- Lifespan: improves
- Healthspan Markers: improves
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Lifespan 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. | Improves (the measure goes up) | Moderate effect | 5 studies | |||
| Healthspan Markers Twice-weekly treatment with humanin analog HNG improved metabolic healthspan parameters and reduced inflammatory markers in middle-aged mice. | Improves (the measure goes up) | Moderate effect | 4 studies |
CJC-1295
- Serum Protein Profile: improves
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Serum Protein Profile Changes in apolipoprotein and immunoglobulin levels | Improves (the measure goes up) | Moderate effect | 16 studies | 11 people |
Epitalon
- Telomere Length: improves
- Telomerase Activity: improves
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Telomere Length Small increase in telomere length observed | Improves (the measure goes up) | Small effect | 3 studies | 45 people | ||
| Telomerase Activity Moderate increase in telomerase activation | Improves (the measure goes up) | Moderate effect | 1 study | 85 people |
What the published studies found
4 automated readings
Calcium: bone mineral density
The studies disagree. The best available review (2022, 7 studies, 1,566 people) found little or no difference in bone mineral density, while 2 of the 3 studies read found an improvement. The evidence is very weak.
3 studies counted of 11 read: 3 reviews.
- Meta-analysis, 2022; 7 studies, 1,566 people; pregnant women and their offspring: no clear difference (the review the verdict rests on).
No advantage of calcium supplementation was found
Calcium supplementation during pregnancy and maternal and offspring bone health: a systematic review and meta-analysis - Systematic review, 2022; 7 studies, 703 people; people taking TDF-based drugs: improves.
significant increase of BMD in the spine and hip
Vitamin D and Calcium Supplementation Reverses Tenofovir-Caused Bone Mineral Density Loss in People Taking ART or PrEP: A Systematic Review and Meta-Analysis - Meta-analysis, 2017; 17 studies, 2,537 people; postmenopausal women: improves. Quantitative analysis of efficacy and associated factors of calcium intake on bone mineral density in postmenopausal women
- Meta-analysis, 2022; 7 studies, 1,566 people; pregnant women and their offspring: no clear difference (the review the verdict rests on).
Nicotinamide Riboside: all-cause mortality
The studies read are too weak to tell whether Nicotinamide Riboside changes all-cause mortality. They lean toward an improvement, which is not enough to claim one. The evidence is very weak.
1 study counted of 8 read.
- Study, 2024; mice with systemic frataxin knockdown: improves.
riboside to shFxn mice increases survival
NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia
- Study, 2024; mice with systemic frataxin knockdown: improves.
Resveratrol: all-cause mortality
The studies read are too weak to tell whether Resveratrol changes all-cause mortality. The strongest review read studied adults with type 2 diabetes mellitus. The evidence is very weak.
1 study counted of 10 read: 1 review.
- Meta-analysis, 2020; 3 studies, 50 people; adults with type 2 diabetes mellitus: unclear: evidence too weak to tell (the review the verdict rests on).
indicating that no deaths occurred (very low-quality evidence for adverse events, all-cause mortality, and diabetes-related …
Resveratrol for adults with type 2 diabetes mellitus
- Meta-analysis, 2020; 3 studies, 50 people; adults with type 2 diabetes mellitus: unclear: evidence too weak to tell (the review the verdict rests on).
Whey Protein: all-cause mortality
The studies read are too weak to tell whether Whey Protein changes all-cause mortality. The evidence is very weak.
1 study counted of 11 read: 1 trial (218 people in the trials).
- Randomised trial, 2020; 218 people; older community-dwelling people with sarcopenia: no clear difference.
Differences were found neither in the all-cause mortality
Effect of Protein Supplementation on Physical Performance in Older People With Sarcopenia-A Randomized Controlled Trial
- Randomised trial, 2020; 218 people; older community-dwelling people with sarcopenia: no clear difference.
Key findings
- Cellular NAD+ LevelsImproves (the measure goes up)
- Senescent Cell MarkersImproves (the measure goes down)
- Physical Function in ElderlyImproves (the measure goes up)
Shop the evidence-backed picks
The collection holds the supplements we grade A or B for its theme, in third-party tested products where the catalog has them. It opens in our Fullscript store. You can look through it without signing in; Fullscript asks for a free account to order.
We earn from purchases made in our Fullscript store, and links to Fullscript, iHerb or Thorne carry our referral, so we may earn a commission at no extra cost to you. Grades come from the research and never change based on what we earn. Full disclosure
Studies cited
100 studies from PubMed
- Analysis of growth hormone releasing hormone and its analogs in urine using nano liquid chromatography coupled with quadrupole/orbitrap mass spectrometry.
- Overview of Epitalon-Highly Bioactive Pineal Tetrapeptide with Promising Properties
- The Antioxidant Tetrapeptide Epitalon Enhances Delayed Wound Healing in an in Vitro Model of Diabetic Retinopathy.
- Plasma Humanin and Non-Coding RNAs as Biomarkers of Endothelial Dysfunction in Rheumatoid Arthritis: A Pilot Study.
- Humanin attenuates metabolic, toxic, and traumatic neuropathic pain in mice by protecting against oxidative stress and increasing inflammatory cytokine.
- HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation.
- Maral Root Extract and Its Main Constituent 20-Hydroxyecdysone Enhance Stress Resilience in Caenorhabditis elegans
- Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes
- MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction.
- MOTS-c in type 2 diabetes mellitus: From risk factors to cardiac complications and potential treatment.
- MOTS-c mimics remote ischemic preconditioning in protecting against lung ischemia-reperfusion injury by alleviating endothelial barrier dysfunction.
- MOTS-c as a Potential Diagnostic-prognostic Biomarker for Myocardial Infarction.
- MOTS-c relieves hepatocellular carcinoma resistance to TRAIL-induced apoptosis under hypoxic conditions by activating MEF2A.
- MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes.
- A mitochondrial-derived peptide MOTS-c contributes to the protective effect against brain injury associated with LPS-induced sepsis by strengthening the blood-brain barrier's ultrastructure.
- MOTS-c attenuates airway barrier dysfunction in allergic asthma by inhibiting epithelial apoptosis via Nrf2 pathway.
- MOTS-c Promotes Glycolysis via AMPK-HIF-1α-PFKFB3 Pathway to Ameliorate Cardiopulmonary Bypass-induced Lung Injury.
- A Mighty Mitochondrial Microprotein: The Protective Role of MOTS-c in Acute Lung Injury.
- MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3.
- The Effects of Fisetin on Reducing Biological Aging: A Pilot Study
- Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial
- [Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6.
- Impaired Expression of Humanin during Adrenocortical Carcinoma.
- Humanin ameliorates TBI-related cognitive impairment by attenuating mitochondrial dysfunction and inflammation.
- Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology.
- Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms.
- Humanin's impact on pain markers and neuronal viability in diabetic neuropathy model.
- Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.
- The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study.
- MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated mitochondrial biogenesis.
- Expression Patterns of MOTS-c in Adrenal Tumors: Results from a Preliminary Study.
- Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination.
- Neuroprotective Mechanism of MOTS-c in TBI Mice: Insights from Integrated Transcriptomic and Metabolomic Analyses.
- Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial biogenesis.
- The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
- The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis.
- Humanin and Its Pathophysiological Roles in Aging: A Systematic Review
- A novel link between chronic inflammation and humanin regulation in children.
- Mitochondrial stress and mitokines in aging.
- Humanin and Its Pathophysiological Roles in Aging: A Systematic Review.
- S14G-humanin confers cardioprotective effects against chronic adrenergic and pressure overload-induced heart failure in mice.
- S14G-humanin alleviates acute lung injury by inhibiting the activation of NF-κB.
- Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases
- Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging
- The protective effect of the mitochondrial-derived peptide MOTS-c on LPS-induced septic cardiomyopathy.
- MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake-A Preliminary Study.
- Orally administered MOTS-c analogue ameliorates dextran sulfate sodium-induced colitis by inhibiting inflammation and apoptosis.
- MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats.
- The mitochondrial-derived peptide MOTS-c suppresses ferroptosis and alleviates acute lung injury induced by myocardial ischemia reperfusion via PPARγ signaling pathway.
- The role of MOTS-c-mediated antioxidant defense in aerobic exercise alleviating diabetic myocardial injury.
- Circulating levels of mitochondrial oxidative stress-related peptides MOTS-c and Romo1 in stable COPD: A cross-sectional study.
- The Mitochondrial-Derived Peptide (MOTS-c) Interacted with Nrf2 to Defend the Antioxidant System to Protect Dopaminergic Neurons Against Rotenone Exposure.
- Adropin and MOTS-c as new peptides: Do levels change in neurodegenerative diseases and ischemic stroke?
- Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function.
- Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway.
- MOTS-c: A potential anti-pulmonary fibrosis factor derived by mitochondria.
- Early detection of cannabinoids in biological samples based on their affinity interaction with the growth hormone secretagogue receptor.
- An antibody-free, ultrafiltration-based assay for the detection of growth hormone-releasing hormones in urine at low pg/mL concentrations using nanoLC-HRMS/MS.
- Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line.
- Epitalon protects against post-ovulatory aging-related damage of mouse oocytes in vitro.
- The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
- Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection
- Humanin and diabetes mellitus: A review of in vitro and in vivo studies.
- The protective effects of S14G-humanin on gestational diabetes mellitus symptoms.
- Humanin vivoliver and tumor bioimpedance measured with biopsy needle.
- An evidence of Humanin-like peptide and Humanin mediated cryosurvival of spermatozoa in buffalo bulls.
- Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD).
- [Gly14]-Humanin inhibits an angiotensin II-induced vascular smooth muscle cell phenotypic switch via ameliorating intracellular oxidative stress.
- Circulating humanin is lower in coronary artery disease and is a prognostic biomarker for major cardiac events in humans.
- Cardio-protective role of Humanin in myocardial ischemia-reperfusion.
- Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension.
- MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases
- The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance.
- MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose.
- MOTS-c promotes muscle differentiation in vitro.
- The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus.
- The Mitochondrial-Derived Peptide MOTS-c Attenuates Oxidative Stress Injury and the Inflammatory Response of H9c2 Cells Through the Nrf2/ARE and NF-κB Pathways.
- MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats.
- Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice.
- MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats.
- Circulating levels of MOTS-c in patients with breast cancer treated with metformin.
- The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
- Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing.
- Nicotinamide Adenine Dinucleotide in the Development and Treatment of Cardiac Remodeling and Aging.
- Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial.
- Advances in the detection of growth hormone releasing hormone synthetic analogs.
- Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era
- Neuroprotective Effect of Fisetin Against the Cerebral Ischemia-Reperfusion Damage via Suppression of Oxidative Stress and Inflammatory Parameters
- Humanin and Alzheimer's Disease: The Beginning of a New Field
- Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases
- Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study.
- Humanin: A mitochondrial-derived peptide in the treatment of apoptosis-related diseases.
- Humanin regulates oxidative stress in the ovaries of polycystic ovary syndrome patients via the Keap1/Nrf2 pathway.
- Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases.
- Mitochondrial humanin peptide acts as a cytoprotective factor in granulosa cell survival.
- MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
- MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway
- MOTS-c reduces myostatin and muscle atrophy signaling
- MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.
- MOTS-c reduces myostatin and muscle atrophy signaling.