HoldsUp

Mark Hyman, MD · 2025-06-25 · Mark Hyman (host), Anurag Singh

Longevity Scientist: Can This Supplement Really Reverse Aging?

48 claims checked against research: 3 contradicted 9 overstated 3 needing context 28 supported 5 unverified

28

Supported by research

0:00:10Anurag Singhsupportedmoderate

Placebo-controlled randomized trials show that supplementation with a bacterial-derived postbiotic yields a 10% to 12% improvement in strength and an approximate 10% improvement in VO2 levels in the absence of exercise or dietary changes.

"Mostly the trials we have run in placebo-controlled randomized trials, we see in the absence of exercise, in the absence of changing their diets, you get about a 10-12% improvement in strength, you get about a 10% improvement in VO2 levels." (said at 0:00:10)

A placebo-controlled randomized trial in middle-aged adults evaluating daily supplementation with Urolithin A (a gut bacterial-derived postbiotic) without concomitant exercise or dietary intervention demonstrated a ~12% increase in muscle strength and significant improvements in aerobic endurance measured as peak oxygen consumption (VO2 peak). While these findings directly support the speaker's statement, certainty is moderate because the evidence comes from limited RCTs in specific populations.

0:10:05Mark Hyman (host)supportedmoderate

VO2 max has a direct linear relationship with longevity and serves as one of the strongest predictors of lifespan.

"What we do know is that VO2 max, which is basically how much oxygen you consume per minute per per kilogram of body weight, is one of the best predictors of longevity. It's in a linear way. The higher the number, I mean, the more fit you are, the more your mitochondria can, you know, consume oxygen and produce energy, the longer you're going to live." (said at 0:10:05)

Extensive observational cohort evidence and meta-analyses support the statement that cardiorespiratory fitness (quantified via VO2 max or exercise capacity in METs) is one of the strongest predictors of all-cause mortality and longevity. A 2024 umbrella review of 199 cohort studies (20.9 million observations) and a dose-response meta-analysis demonstrated a continuous, inverse dose-response relationship between cardiorespiratory fitness and all-cause mortality, where each 1-MET increment in fitness is associated with an 11% to 17% reduction in mortality risk. Furthermore, a large cohort study of 122,007 patients found no observed upper threshold of benefit, with elite performers exhibiting the lowest risk of death compared to all other performance tiers.

0:11:17Mark Hyman (host)supportedmoderate

Autism spectrum disorder is driven in part by mitochondrial dysfunction and a cerebral energy deficit.

"autism, you know, is found to have been really in part driven by mitochondrial dysfunction in these kids. They have a brain energy deficit, and Suzanne Goh showed this, who's a Harvard, Oxford-trained pediatric neurologist." (said at 0:11:17)

Published neuroimaging and biomarker studies confirm that mitochondrial dysfunction and associated energetic deficits affect a subset of individuals with autism spectrum disorder (ASD). Research led by Dr. Suzanne Goh using brain magnetic resonance spectroscopic imaging demonstrated elevated brain lactate (a biomarker of mitochondrial impairment and altered energy metabolism) in a distinct subgroup of ASD individuals compared to controls. Subsequent systematic reviews and meta-analyses corroborate that mitochondrial abnormalities, altered energetic metabolites, and elevated lactate levels are prevalent in a subgroup (approximately 15–30%) of individuals with ASD.

0:14:23Anurag Singhsupportedhigh

Mitochondrial DNA leaking into circulation from damaged mitochondria stimulates inflammatory pathways.

"Really, these damaged mitochondria that become leaky, and the damaged mitochondrial DNA—I mean, mitochondria have their own DNA that leaks out into the circulation and causes, you know, inflammation." (said at 0:14:23)

The speaker's statement accurately reflects a well-established biological mechanism. Mitochondria possess their own circular DNA (mtDNA). When mitochondrial integrity is compromised through damage, stress, or cell death, mtDNA can leak into the cytosol, extracellular space, and systemic circulation. Because of its evolutionary similarity to bacterial DNA (such as unmethylated CpG motifs), circulating cell-free mtDNA acts as a damage-associated molecular pattern (DAMP). It is recognized by innate immune sensors including Toll-like receptor 9 (TLR9), the cGAS-STING pathway, and the NLRP3 inflammasome, triggering the production and release of pro-inflammatory cytokines and driving systemic inflammation.

0:22:06Anurag Singhsupportedvery low

Exposing muscle cells or other cell types to sodium fluoride causes cellular stress in mitochondria.

"We see that actually if you put some sodium fluoride on muscle cells or any kind of cells, the mitochondria get stressed." (said at 0:22:06)

In vitro and animal experimental models demonstrate that exposure to sodium fluoride induces mitochondrial stress and dysfunction across various cell types. Experimental studies measuring mitochondrial bioenergetics show that sodium fluoride exposure triggers excessive mitochondrial reactive oxygen species (ROS) production, disrupts mitochondrial membrane potential, causes mitochondrial calcium overload, and impairs basal and maximal mitochondrial respiration and ATP production.

0:17:08Anurag Singhsupportedhigh

Exercise activates the PGC-1alpha pathway to stimulate mitochondrial biogenesis and the production of new mitochondria.

"this is the whole PGC-1alpha pathway where, you know, where you stimulate this mitochondrial biogenesis, you can improve the growth of new mitochondria." (said at 0:17:08)

The speaker's statement accurately describes a foundational principle of exercise physiology and molecular metabolism. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is activated in skeletal muscle by exercise (via upstream energy-sensing pathways like AMPK and SIRT1) and coordinates the downstream transcription of nuclear and mitochondrial genes required for mitochondrial biogenesis and mitochondrial network remodeling.

0:17:39Anurag Singhsupportedmoderate

Metformin, resveratrol, and NAD boosters promote mitochondrial biogenesis by targeting the AMPK pathway.

"you have these NAD boosters, compounds like resveratrol, at least from a nutrition perspective, or metformin, they're all hitting this sort of AMPK mitochondrial biogenesis pathway." (said at 0:17:39)

Metformin, resveratrol, and NAD-enhancing strategies are well-documented to converge on the interconnected AMPK/SIRT1/PGC-1α signaling network that orchestrates mitochondrial biogenesis. AMPK activation stimulates NAD+ production and SIRT1 deacetylation of PGC-1α, a master transcriptional coactivator of mitochondrial biogenesis, establishing a core positive feedback loop across metabolic regulation.

0:23:58Mark Hyman (host)supportedhigh

The human gut microbiome contains approximately two million genes, about one hundred times more genetic material than the roughly 20,000 human genes.

"And you have probably a hundred times as much bacterial DNA as your own DNA, because you've got a thousand species, they're all different, they all have different DNA. You know, we might have 20,000 genes; there might be two million bacterial genes." (said at 0:23:58)

Metagenomic sequencing of the human gut microbiome has identified millions of non-redundant microbial genes—initially catalogued at approximately 3.3 million genes across 124 individuals, which is roughly 150 times larger than the ~20,000 to 25,000 protein-coding genes in the human genome. The speaker's approximation of around 2 million bacterial genes (about 100 times more than the roughly 20,000 human genes across ~1,000 species) accurately reflects this established scientific finding.

  • supports: A human gut microbial gene catalogue established by metagenomic sequencing. (Nature 2010) · cited 11824x in the literature
    "Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes." (abstract, passage verified)
    pubmedfull study (doi)
0:33:46Mark Hyman (host)supportedhigh

The Recommended Dietary Allowance (RDA) for protein is 0.8 grams per kilogram of body weight.

"Because the RDA is 0.8 grams per kilo, which is the minimum you need to prevent a deficiency of protein, but not maximum amount you need for optimal health." (said at 0:33:46)

The Recommended Dietary Allowance (RDA) for dietary protein in adults is established at 0.8 grams per kilogram of body weight per day. Established via nitrogen balance studies, the RDA represents the minimum daily intake necessary to prevent deficiency and avoid a net loss of body protein, rather than the level required for optimal health or muscle maintenance.

0:34:59Mark Hyman (host)supportedhigh

Animal protein sources provide higher levels of leucine, the amino acid necessary to stimulate muscle protein synthesis, compared to plant protein sources.

"But if you use animal protein, you're going to get a much more concentrated protein at a lower calorie count and also with higher levels of leucine, which is the amino acid you need to actually make muscle." (said at 0:34:59)

Animal protein sources generally provide higher protein density per calorie and higher concentrations of essential amino acids, particularly leucine, compared to most plant-based protein sources. Leucine is well established as the key trigger for activating the mTOR pathway to stimulate muscle protein synthesis (MPS). While certain isolated or blended plant proteins (e.g., corn isolate or leucine-fortified blends) can match the leucine threshold, typical whole-food plant proteins have lower leucine concentrations, lower digestibility, and less concentrated protein per caloric intake than animal proteins.

0:40:09Anurag Singhsupportedmoderate

Urolithin A is a metabolite produced by the gut microbiome from dietary polyphenols and ellagitannins found in foods like pomegranates.

"So what we discovered was that this molecule, urolithin A, is actually not a waste product. It's actually a very potent gut metabolite produced by the gut microbiome that has these immense rejuvenation effects on mitochondria." (said at 0:40:09)

Published research confirms that urolithin A is a postbiotic gut microbial metabolite synthesized by the gut microbiota from dietary precursors, specifically ellagitannins and ellagic acid found in foods such as pomegranates, nuts, and berries. Preclinical and human clinical studies demonstrate that urolithin A stimulates mitophagy (the selective degradation and recycling of damaged mitochondria) and mitochondrial biogenesis, which enhances mitochondrial function and muscle endurance.

0:41:30Anurag Singhsupportedhigh

Placebo-controlled randomized trials show that urolithin A supplementation leads to approximately a 10% to 12% improvement in muscle strength, a 10% increase in VO2 levels, and lower inflammation without changes in exercise or diet.

"Mostly the trials we've run in in placebo-controlled randomized trials, we see in the absence of exercise, in the absence of changing their diets, you get about a 10, 12% improvement in strength, you get about a 10% improvement in VO2 levels. So this aerobic endurance we talked about, and you also get lower inflammation." (said at 0:41:30)

Randomized, placebo-controlled clinical trials support the claim. In middle-aged adults (40–65 years old), four months of daily Urolithin A (Mitopure) supplementation without exercise or dietary changes led to a statistically significant ~12% improvement in muscle strength, improvements in aerobic endurance/peak VO2, and significant reductions in C-reactive protein (CRP), indicating reduced systemic inflammation. Similar reductions in inflammatory markers (CRP) and improvements in muscle endurance were also demonstrated in a separate 4-month randomized controlled trial in older adults.

0:47:42Anurag Singhsupportedmoderate

A clinical trial administering urolithin A for one month to healthy 40- to 50-year-olds profiling over 80 immune populations showed an increase in age-declining immune cells (such as T cells and NK cells) containing higher numbers of mitochondria and enhanced pathogen-killing capacity.

"And he said, 'Well, let's do a trial where we give this molecule for a month to healthy 40, 50-year-olds and we look at every single immune cell in the body, at the impact it's causing and the mitochondria in it.'... What we actually now find with supplementation is that a lot of these immune cells that are declining with aging, they come back with Mitopure supplementation. And when they come back, they have more mitochondria... And these immune cells are more wired to fight infection. So if you throw an infection on them, they engulf it and kill it much faster." (said at 0:47:42)

A double-blind, randomized, placebo-controlled clinical trial in 50 healthy middle-aged adults evaluated 4 weeks (1 month) of oral urolithin A (1,000 mg/day) supplementation. The trial found that urolithin A supplementation expanded naive-like CD8+ T cells and peripheral NK cell subsets, augmented mitochondrial biogenesis in CD8+ T cells, improved T-cell cytokine activation, and enhanced bacterial phagocytosis (uptake) in monocytes.

0:30:44Anurag Singhsupportedhigh

High-intensity training and aerobic training have a greater impact on improving mitochondrial health than resistance training.

"Resistance training less so as something like high-intensity training or aerobic training in terms of the impact on mitochondrial health." (said at 0:30:44)

The speaker's claim is supported by exercise physiology literature. Aerobic training and high-intensity interval training are well-established primary stimuli for mitochondrial biogenesis, oxidative enzyme activity, and mitochondrial respiratory capacity in skeletal muscle, primarily through activation of the AMPK-PGC-1α signaling cascade. While resistance training can induce modest mitochondrial improvements (particularly under high-volume or low-load paradigms), its primary adaptive priority and physiological signaling pathways (such as mTORC1) drive myofibrillar protein synthesis, muscle hypertrophy, and ribosome biogenesis rather than substantial mitochondrial remodeling.

1:25:29Mark Hyman (host)supportedhigh

Metformin inhibits mitochondrial complex I, which interferes with mitochondrial function.

"one of the consequences of metformin is that it inhibits mitochondrial complex I, which while it seems like it helps with blood sugar and many things you'd want to have it help with, it also interferes with mitochondrial function" (said at 1:25:29)

A primary and well-established mechanism of action of metformin is the mild inhibition of mitochondrial complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain. This inhibition disrupts standard mitochondrial respiratory chain function, altering the cellular AMP-to-ATP ratio, activating AMP-activated protein kinase (AMPK), reducing hepatic gluconeogenesis, and enhancing intestinal glucose uptake, thereby lowering blood glucose levels.

1:29:16Anurag Singhsupportedvery low

In animal models of heart failure, Mitopure (Urolithin A) supplementation reversed cardiac damage by improving mitochondrial health.

"we went into models of heart failure, acute and chronic, and we found that giving Mitopure supplementation in these models reversed a lot of this cardiac damage by improving mitochondrial health." (said at 1:29:16)

Preclinical studies in animal models of heart failure and cardiac aging support the claim. Research shows that Urolithin A (Mitopure) supplementation reduces cardiac dysfunction, hypertrophy, and fibrosis while restoring mitochondrial ultrastructure, respiration, and mitophagy. Because these findings are established in animal and cellular models, the certainty of evidence for clinical human efficacy in heart failure remains very low.

1:30:00Anurag Singhsupportedmoderate

In clinical trials, Mitopure supplementation reduces plasma levels of ceramides in humans.

"And what we see is actually in all our trials, plasma levels of ceramides are going down." (said at 1:30:00)

Randomized controlled trials evaluating urolithin A (Mitopure) supplementation in older adults have demonstrated reductions in circulating plasma ceramide levels. In a double-blind, placebo-controlled clinical trial (PMID 35050355), four months of oral urolithin A supplementation significantly decreased plasma levels of several ceramides, acylcarnitines, and C-reactive protein compared with placebo. Subsequent analyses and human trials (PMID 40034121) similarly report that four months of urolithin A supplementation reduces cardiovascular-risk-associated plasma ceramides.

1:30:30Anurag Singhsupportedmoderate

The Mayo Clinic has a clinical ceramide score that predicts cardiovascular disease prognosis.

"there's the Mayo Clinic that has now a score of ceramides that allows you to predict the prognosis of cardiovascular health." (said at 1:30:30)

Mayo Clinic researchers developed and clinically implemented a plasma ceramide risk score (evaluating circulating ceramides such as Cer(16:0), Cer(18:0), and Cer(24:1) along with their ratios to Cer(24:0)) to assess cardiovascular risk. Prospective cohort studies have demonstrated that higher ceramide risk scores independently predict major adverse cardiovascular events (including myocardial infarction, stroke, and cardiovascular mortality) even after adjusting for standard lipid panels and traditional cardiovascular risk factors.

1:30:50Anurag Singhsupportedmoderate

Mitopure (Urolithin A) supplementation improves VO2 max in humans.

"But we do know things like VO2 max improve with Mitopure, which is also cardiovascular health." (said at 1:30:50)

A double-blind, randomized, placebo-controlled trial evaluating Urolithin A (Mitopure) supplementation in middle-aged adults demonstrated improvements in aerobic endurance measured by peak oxygen consumption (peak VO2) and 6-minute walk distance, alongside improvements in muscle strength and mitochondrial biomarkers. In trained male distance runners, supplementation also led to significant within-group increases in VO2 max, although between-group differences compared to placebo during altitude training camp did not reach statistical significance.

1:35:07Anurag Singhsupportedmoderate

Skin fibroblasts and keratinocytes accumulate mitochondrial damage with aging.

"skin cells in the fibroblasts or the keratinocytes—these are the two main cells in the epidermis and the dermis—they have lots of mitochondria. And over aging, over time of adult healthspan, they get damaged in much the same way as muscle and brain cells do." (said at 1:35:07)

Skin fibroblasts (in the dermis) and keratinocytes (in the epidermis) accumulate mitochondrial damage and dysfunction over chronological aging and photoaging. Published literature demonstrates that advancing age and cumulative environmental stressors lead to mitochondrial DNA (mtDNA) damage, impaired oxidative phosphorylation, elevated reactive oxygen species (ROS), and defective mitophagy in cutaneous cells, mirroring aging pathways observed in high-energy metabolic tissues.

1:48:38Anurag Singhsupportedmoderate

Statins deplete the electron transport chain and cause coenzyme Q10 deficiency.

"At a higher level, they are mitochondrial toxins, and they deplete the electron transport chain, and CoQ10 deficiency happens." (said at 1:48:38)

Statins inhibit HMG-CoA reductase, an upstream enzyme in the mevalonate pathway required for the biosynthesis of coenzyme Q10 (CoQ10/ubiquinone), an essential electron carrier in the mitochondrial electron transport chain. A systematic review and meta-analysis of randomized placebo-controlled trials confirmed that statin therapy significantly reduces circulating CoQ10 concentrations across all statin classes (WMD: -0.44 μmol/L, 95% CI: -0.52 to -0.37). In addition, in vitro and preclinical studies demonstrate that higher concentrations of statins exhibit mitochondrial toxicity by inhibiting electron transport chain complexes (such as Complex I and III) and impairing oxidative phosphorylation, mechanisms implicated in statin-induced myopathy.

1:50:09Mark Hyman (host)supportedhigh

The mevalonate pathway that synthesizes cholesterol also produces coenzyme Q10.

"the same pathway that makes your LDL cholesterol also makes coenzyme Q10, which is one of the mitochondrial helpers, cofactors." (said at 1:50:09)

The mevalonate pathway (initiated by HMG-CoA reductase) is responsible for the endogenous biosynthesis of cholesterol and also generates isoprenoid intermediates (such as farnesyl pyrophosphate) required for the synthesis of coenzyme Q10 (ubiquinone), an essential cofactor in the mitochondrial electron transport chain.

1:29:16Anurag Singhsupportedmoderate

Cardiac biopsies from patients who have heart failure or died of cardiac degeneration show poor mitochondrial health as a hallmark signature.

"they actually looked at cardiac biopsies of people who had heart failure or had died of heart degeneration and with the aging process. And again, the signature, the hallmark signature they picked up in the heart was poor mitochondrial health." (said at 1:29:16)

Published clinical and histopathological studies evaluating human myocardial biopsies confirm that mitochondrial abnormalities and dysfunction are hallmark signatures of cardiac degeneration, aging, and heart failure. In patients undergoing endomyocardial biopsies for heart failure, structural and functional mitochondrial impairments (such as cristae disorganization and membrane disruption) are prominent features that correlate strongly with disease severity, impaired reverse remodeling, and adverse cardiovascular outcomes.

1:36:00Anurag Singhsupportedhigh

Matrix metalloproteinases (MMPs) degrade collagen and increase significantly with aging.

"And there are enzymes called matrix metalloproteinases, MMPs, that degrade collagen that just shoot up with aging." (said at 1:36:00)

Matrix metalloproteinases (MMPs), particularly collagenases such as MMP-1, are enzymes responsible for degrading collagen fibrils in human extracellular matrix. Extensive human skin tissue and cell culture studies confirm that MMP expression and activity increase significantly with chronological aging and photoaging, driving age-related collagen fragmentation and loss.

1:50:29Anurag Singhsupportedhigh

Coenzyme Q10 has low oral bioavailability.

"CoQ10 is not also a very highly bioavailable compound when taken orally." (said at 1:50:29)

Coenzyme Q10 (CoQ10 / ubiquinone) is well established in pharmacokinetic research to possess poor oral bioavailability. Due to its high molecular weight (863 g/mol), strong lipophilicity/hydrophobicity, and poor aqueous solubility, intestinal absorption of standard oral CoQ10 is slow and limited, prompting extensive pharmaceutical development into specialized delivery systems (such as solubilized, lipid-based, or nanoemulsion formulations) to improve systemic absorption.

1:57:11Anurag Singhsupportedmoderate

Vitamin D has beneficial effects on mitochondrial function and immune cells.

"You know, vitamin D—we didn't talk about that, but also has some great effects on mitochondria and immune cells." (said at 1:57:11)

Published molecular, preclinical, and human experimental studies demonstrate that vitamin D and its active metabolite calcitriol (1,25-dihydroxyvitamin D) exert significant regulatory and protective effects on both mitochondrial function and immune cells. Vitamin D influences mitochondrial energy production, dynamics (fission-fusion), and membrane potential while modulating innate and adaptive immune cell signaling, metabolic reprogramming, and cytokine production.

1:56:42Mark Hyman (host)supportedhigh

Mitochondria originated evolutionarily from bacteria and possess distinct DNA inherited maternally.

"mitochondria historically came from bacteria. So they're basically a symbiotic relationship with bacteria and humans, and they're not the same in terms of their DNA. They're actually quite different than your DNA. They come from your mother, but it's mitochondrial DNA." (said at 1:56:42)

The speaker's statement accurately reflects fundamental biological principles established by extensive evolutionary and genetic evidence. Mitochondria originated through endosymbiosis from ancestral α-proteobacteria, establishing a symbiotic relationship within eukaryotic cells. Mitochondria maintain their own distinct genome (mitochondrial DNA, or mtDNA), which is separate from nuclear chromosomal DNA and is strictly inherited through maternal lineage in humans.

1:57:42Anurag Singhsupportedmoderate

Studies demonstrate that antibiotics act as mitochondrial stressors.

"There's enough studies showing they're mitochondrial stressors. Now, I think it really depends on the duration of usage, the dose, and certain classes of antibiotics are probably worse off than the others." (said at 1:57:42)

The statement that studies demonstrate antibiotics act as mitochondrial stressors—with effects depending on duration, dose, and antibiotic class—is supported by published literature. Due to the shared evolutionary origin between mitochondria and bacteria, several major classes of antibiotics (such as aminoglycosides, fluoroquinolones, macrolides, and oxazolidinones like linezolid) can inhibit mitochondrial protein synthesis or electron transport chain activity. A landmark study demonstrated that clinically relevant concentrations of bactericidal antibiotics (quinolones, aminoglycosides, and beta-lactams) induce mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and oxidative damage in mammalian cells and animal models. Furthermore, clinical investigations in humans show that prolonged exposure to specific agents, such as linezolid, induces progressive mitochondrial respiratory impairment in a duration-dependent manner.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.