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
- 41 studies cited
- Supplements studied
- 4
- Medicines and peptides
- 4
- Graded outcomes
- 13
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
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Longevity | 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 | 9 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 | 3 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 | 2 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 | 14 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)
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Studies cited
41 studies from PubMed
- 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
- The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis.
- Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging
- Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases
- Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing.
- The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
- MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases
- Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.
- NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.
- 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
- The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan
- Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions.
- Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD(+) Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.
- Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence.
- Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals
- Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance
- Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.
- NAD⁺ in aging, metabolism, and neurodegeneration.
- The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
- NAD+ and sirtuins in aging and disease.
- Protective effects of [Gly14]-Humanin on beta-amyloid-induced PC12 cell death by preventing mitochondrial dysfunction
- Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway.
- Activation of the GH/IGF-1 axis by CJC-1295, a long-acting GHRH analog, results in serum protein profile changes in normal adult subjects
- Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells
- Aging of the pineal gland
- Peptides and Ageing
- Clinical interventions with various agents to prevent early childhood caries: A systematic review with network meta-analysis.
- Fluorides for preventing early tooth decay (demineralised lesions) during fixed brace treatment.
- Screening and Interventions to Prevent Dental Caries in Children Younger Than 5 Years: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.
- Fluoride toothpastes of different concentrations for preventing dental caries.
- Comparative study of Kefir yogurt-drink and sodium fluoride mouth rinse on salivary mutans streptococci
- Effects of probiotics on salivary Streptecoccus mutans and Lactobacillus levels in orthodontic patients
- The effect of systemic zinc supplementation on oral health in low socioeconomic level children
- A clinical investigation to evaluate reduction in dental stain provided by the once-daily use of a breath mint or chewing gum
- Effects of a Baking Soda Gum on extrinsic dental stain: results of a longitudinal 4-week assessment
- Efficacy of baking soda-containing chewing gum in removing natural tooth stain
- Effects of passiflora incarnata and midazolam for control of anxiety in patients undergoing dental extraction.
- Herbal medicines as anxiolytics prior to third molar surgical extraction. A randomized controlled clinical trial.
- Effect of a sugar-free chewing gum containing magnolia bark extract on different variables related to caries and gingivitis: a randomized controlled intervention trial
- Preliminary evidence hints at a protective role for boron in urolithiasis