HoldsUp

FoundMyFitness · 2022-04-12 · Rhonda Patrick (host), Morgan Levine

Morgan Levine, PhD, on PhenoAge and the Epigenetics of Age Acceleration — can we change the pace?

52 research-tied claims examined: 1 contradicted 1 overstated 1 context 45 supported 4 unverified

1

Contradicted by research

0:20:38Morgan Levinecontradictedmoderate

Genetics is estimated to account for only about 10% to at most 20% of variation in epigenetic aging rates.

"So I think they estimate like 10, maybe at the uppermost 20 percent impact your genes have on your epigenetic aging rate." (said at 0:20:38)

Twin and pedigree-based quantitative genetic studies consistently show that the heritability of epigenetic aging and epigenetic age acceleration (the discrepancy between chronological age and DNA methylation age) is substantially higher than 10% to 20%. Pedigree analyses estimate the heritability of epigenetic age acceleration (Δage) at approximately 43% (e.g., Marioni et al., 2015), and twin studies across multiple clocks (such as Horvath, Hannum, PhenoAge, and GrimAge) typically report heritability estimates ranging from roughly 35% to 60% in young and older adults, though heritability can decline in later decades of life. The speaker's claim that genetics accounts for only 10% to at most 20% of variation in epigenetic aging rates substantially underestimates the established genetic contribution.

1

Overstated

1:05:09Morgan Levineoverstatedmoderate

A statistical method that removes technical noise reduces the test-retest variation of split samples on epigenetic clocks to a maximum difference of about one year.

"we actually developed a statistical method that completely removes all this technical noise. And I won't go into the math for people on the podcast, but basically, we can get this down to: you can split the sample, and now you're getting only about one year difference at max." (said at 1:05:09)

A 2022 study by Higgins-Chen, Levine, and colleagues introduced principal-component-based (PC) epigenetic clocks to address technical noise in DNA methylation assays. In their validation across six prominent epigenetic clocks, the PC approach significantly reduced technical noise between split-sample replicates (from discrepancies of up to 9 years down to agreement for most replicates within 1.5 years). However, the claim that the method "completely removes all" technical noise and restricts differences to "at max" about one year overstates the findings, as residual variation remains and 1.5 years reflected the range for most, but not strictly all, replicates.

  • partial: A computational solution for bolstering reliability of epigenetic clocks: Implications for… (Nature aging 2022) · cited 527x in the literature
    "Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro ." (abstract, results, passage verified)
    pubmedfull study (doi)
1

Needs context

1:01:07Rhonda Patrick (host)needs contextlow

In Framingham data, smokers with a high omega-3 index had the same life expectancy as non-smokers with a low omega-3 index.

"the smokers that took high omega-3 had the same life expectancy as the non-smokers with low omega-3." (said at 1:01:07)

In an observational analysis of the Framingham Offspring Cohort (n = 2,240, median follow-up 11 years) published by McBurney and colleagues in 2021, participants with higher baseline red blood cell Omega-3 Index (O3I) had lower all-cause mortality. In survival modeling comparing combinations of smoking status and O3I, smokers with a high O3I had a predicted survival probability comparable to non-smokers with a low O3I (both translating to roughly a 4.7-year loss in predicted remaining life expectancy compared to high-O3I non-smokers). However, these findings represent observational associations of erythrocyte membrane levels, not interventional evidence from randomized trials showing that taking omega-3 supplements offsets the mortality risks of smoking.

45

Supported by research

0:07:39Morgan Levinesupportedhigh

With aging, genomic CpG sites that typically have methylation lose it, while CpG sites that typically lack methylation gain it.

"Some of them are supposed to be methylated from the beginning, but what we find with aging is that the ones that we expect to have methylation lose methylation with aging, and the ones that shouldn't have methylation gain methylation with aging." (said at 0:07:39)

The speaker accurately describes a well-established phenomenon in the epigenetics of aging: global hypomethylation paired with locus-specific hypermethylation. In mammalian aging, regions that are normally heavily methylated (such as repetitive transposable elements, heterochromatin, and CpG-poor gene bodies) tend to progressively lose methylation, while regions that are normally unmethylated (notably promoter CpG islands) frequently gain methylation.

0:10:42Morgan Levinesupportedhigh

The PhenoAge epigenetic clock, published in 2018, was trained on clinical lab test markers combined into a mortality-predictive measure rather than directly on chronological age.

"So what the second-generation clocks did—the one that we published in 2018 was the first example—is we said, "Oh, can we come up with a better thing to try and kind of tune these measures to?" So in that case, we used kind of normal lab tests that we combined into a measure that was predictive of mortality, and then we trained a predictor of those lab tests." (said at 0:10:42)

The 2018 paper introducing DNAm PhenoAge by Levine et al. used a two-step process where clinical chemistry lab tests and chronological age were first combined into a composite clinical measure of phenotypic age calibrated to mortality risk, and then DNA methylation data were trained to predict this phenotypic measure rather than chronological age alone.

  • supports: An epigenetic biomarker of aging for lifespan and healthspan. (Aging 2018) · cited 3747x in the literature
    "While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease." (abstract, passage verified)
    pubmedfull study (doi)
0:11:35Morgan Levinesupportedhigh

The GrimAge epigenetic clock was developed by training DNA methylation surrogate predictors of plasma proteins and then training a predictor of mortality.

"And a similar thing was done with the GrimAge clock, where they took these different proteins and they trained predictors of that, and then trained the predictor of mortality." (said at 0:11:35)

The GrimAge epigenetic clock was developed using a two-stage approach: researchers first trained DNA methylation (DNAm) surrogate estimators of specific circulating plasma proteins (such as PAI-1, GDF-15, and others) and smoking pack-years, and then trained a composite model on these DNAm surrogates to predict time-to-death (mortality risk and lifespan).

0:15:44Morgan Levinesupportedmoderate

GrimAge is particularly effective at predicting cardiovascular disease mortality risk.

"GrimAge is particularly good at cardiovascular risk mortality, which is why it does well at all-cause mortality, because that's the biggest killer of people, at least in the United States." (said at 0:15:44)

DNA methylation GrimAge is a composite epigenetic biomarker developed to predict lifespan and mortality risk by integrating DNA methylation surrogates of plasma proteins (e.g., PAI-1, GDF-15, hsCRP) and smoking pack-years. Extensive cohort studies, including original validation data and population studies such as NHANES, demonstrate that GrimAge and GrimAge2 strongly predict cardiovascular disease incidence, cardiovascular disease mortality, and all-cause mortality, consistently outperforming first-generation epigenetic clocks (such as Horvath and Hannum).

0:15:55Morgan Levinesupportedhigh

Cardiovascular disease is the leading cause of death in the United States.

"because that's the biggest killer of people, at least in the United States." (said at 0:15:55)

Epidemiological surveillance data and national vital statistics consistently establish cardiovascular disease (and specifically coronary/ischemic heart disease) as the leading cause of death in the United States, accounting for more than one out of every four deaths.

0:21:15Morgan Levinesupportedmoderate

Smoking accelerates epigenetic age in epidemiological studies.

"So socioeconomic status is a big thing in terms of differences in epigenetic age, but also behaviors: so smoking really accelerates your epigenetic age" (said at 0:21:15)

Epidemiological cohort studies consistently demonstrate that cigarette smoking is strongly associated with accelerated epigenetic aging across various DNA methylation clocks (such as GrimAge, PhenoAge, and DunedinPACE). In representative population studies such as NHANES, current smoking is associated with substantial epigenetic age acceleration (e.g., up to ~9 to 10 years higher GrimAge compared to never smokers) in a dose-dependent manner, while smoking cessation is associated with progressive attenuation of this acceleration over time.

0:21:29Morgan Levinesupportedmoderate

Physical exercise tends to decrease epigenetic age.

"generally exercise will tend to decrease epigenetic age" (said at 0:21:29)

A systematic review and meta-analysis of 44 studies (145,465 participants) evaluated the relationship between physical activity and biological age measured by DNA methylation clocks. The meta-analysis found that higher physical activity was significantly associated with lower epigenetic age acceleration across major clocks, including Horvath EAA (β = -0.03 SD per SD increase in MET-min/week) and GrimAge EAA (β = -0.09 SD). Large cohort studies (such as the Health and Retirement Study) similarly report that physically active adults demonstrate lower epigenetic age acceleration across multiple second-generation clocks (GrimAge, PhenoAge, and DunedinPACE). The speaker's statement that exercise generally tends to decrease epigenetic age accurately reflects the published epidemiological and meta-analytic evidence.

0:22:26Morgan Levinesupportedmoderate

On average, females exhibit lower epigenetic age than chronological age-matched males.

"So on average, not across the board, but if you look at the distributions, females on average will have slower or lower epigenetic age than same chronological age males." (said at 0:22:26)

Multiple large-scale observational studies using various DNA methylation clocks (such as the Horvath, Hannum, and GrimAge clocks) demonstrate that females on average exhibit lower epigenetic age and slower epigenetic age acceleration compared to chronological age-matched males across multiple tissue types (including blood, saliva, and brain tissue).

0:23:00Morgan Levinesupportedmoderate

Natural and surgical menopause are associated with accelerated epigenetic aging.

"So we looked at women who had undergone menopause and how long since they'd undergone menopause, and it seems to be that menopause is actually an epigenetic aging accelerated event. So before menopause, women are doing pretty well, and then when they go through menopause, it seems to accelerate their epigenetic age. And we didn't have the kind of data you would want where we'd have the same women pre- and post-, but we can even look at surgical menopause, and that seems to also show this kind of accelerated epigenetic aging manifestation." (said at 0:23:00)

Large multi-cohort observational analyses and Mendelian randomization studies confirm that both natural menopause (earlier age at menopause and longer time post-menopause) and surgical menopause (bilateral oophorectomy or hysterectomy) are significantly associated with accelerated epigenetic aging measured by DNA methylation clocks.

0:29:10Morgan Levinesupportedmoderate

Research by Vadim Gladyshev suggests human aging begins at approximately day eight of gestation.

"even one of my colleagues at Harvard, Vadim Gladyshev, showing kind of when he thinks this ground zero when aging starts, which is according to him day eight of gestation." (said at 0:29:10)

Research from Vadim Gladyshev's laboratory proposed the concept of 'ground zero'—the point during early embryonic development where biological age reaches its absolute minimum following a post-fertilization rejuvenation event, after which organismal aging begins. Their studies using epigenetic clocks in mouse and human embryogenesis showed that this minimum occurs around gastrulation (approximately day 6.5–8 in mice and during early post-implantation / gastrulation stages in humans), marking the onset of biological aging.

0:28:45Morgan Levinesupportedhigh

Extending the developmental and reproductive period in Drosophila extends their overall lifespan.

"So there are beautiful experiments in flies where if you can extend kind of the developmental period, it extends the lifespan of these animals." (said at 0:28:45)

The claim that extending the developmental period in *Drosophila* extends their overall lifespan is supported by experimental research in fruit flies. For example, genetic manipulation of prothoracicotropic hormone (PTTH) or time-restricted silencing of *Relish* (NF-κB signaling) during larval stages delays developmental timing/pupariation and extends adult lifespan in *Drosophila melanogaster* (PMID: 40339121). Additionally, long-term selective breeding experiments that postpone reproduction and extend developmental/reproductive timing consistently produce *Drosophila* lines with significantly increased lifespans (PMID: 26378456, PMID: 31969430).

0:19:49Rhonda Patrick (host)supportedmoderate

Biological aging measured across multiple physiological biomarkers correlates with perceived facial age in young adults.

"and there was like 18 biomarkers that were looked at, and it was PNAS or something—... And it was like, look at people are aging at different rates, and you can even look at their faces and it correlates with their biological age more than their chronological age." (said at 0:19:49)

A landmark 2015 study from the Dunedin birth cohort published in the Proceedings of the National Academy of Sciences (PNAS) tracked 18 physiological biomarkers across organ systems in 954 young adults at ages 26, 32, and 38. Because all participants were the same chronological age (38 at assessment), differences in biological aging rates could be isolated; individuals with accelerated biological aging were rated as appearing significantly older in facial photographs assessed by independent raters.

0:23:58Morgan Levinesupportedhigh

Mortality risk and frailty index scores increase exponentially after approximately age 30.

"So if you think of a frailty index or even mortality risk, it increases exponentially after let's say age 30." (said at 0:23:58)

The statement accurately reflects well-established demographic and biodemographic principles. Under the Gompertz law of human mortality, the age-specific mortality rate increases exponentially with age throughout adult life (typically starting around age 30, following the post-adolescent mortality trough). Similarly, demographic and geriatric research evaluating the accumulation of health deficits using the Frailty Index (FI) demonstrates that average frailty index scores also increase exponentially with age across adult populations.

0:08:00Morgan Levinesupportedhigh

DNA methylation at CpG sites generally represses gene expression by rendering genomic regions inaccessible, whereas DNA demethylation is associated with active gene transcription.

"The methylation in this is basically turning on or off different parts of your genome. So when you have methylation, we can essentially assume that part is repressed, so that wherever it is in the genome is not accessible, you're not expressing the genes in that region, versus when you remove the methylation, we consider this more an active region." (said at 0:08:00)

The speaker's statement accurately summarizes the fundamental epigenetic paradigm of DNA methylation and demethylation. In general, cytosine methylation (particularly in CpG-rich regulatory regions and transcription start sites) leads to transcriptional repression and heterochromatin formation by physically impeding transcription factor binding and recruiting repressive methyl-CpG-binding domain proteins and chromatin remodeling complexes. Conversely, DNA demethylation or unmethylated promoter regions are characteristic of transcriptionally accessible and active chromatin states.

0:30:01Morgan Levinesupportedvery low

Selecting fruit flies over generations for delayed fecundity results in extended lifespan.

"So they're selecting for flies over generations that are going to be these later fecundity flies, and they show that they also live longer in the end." (said at 0:30:01)

The speaker's statement accurately describes classic and repeated findings in Drosophila experimental evolution. Artificial selection for delayed reproduction (propagating fruit flies from eggs laid at later ages across generations) consistently produces evolutionary lines that exhibit significantly extended lifespan compared to control or early-reproduction lines. Because this finding is based exclusively on laboratory model organism (insect) experiments, the GRADE certainty is rated very low.

0:30:14Rhonda Patrick (host)supportedlow

Immortalizing cells with hTERT overcomes cellular senescence, but their epigenetic age continues to increase with subsequent cell passaging.

"if you take a cell that has not been immortalized in tissue culture, and then you immortalize it with a component of telomerase, hTERT, and you essentially overcome cellular senescence, which is one of the hallmarks of aging, right?... And these cells, if you continue culturing them in tissue culture, their epigenetic age just keeps going, going, and going." (said at 0:30:14)

The host's claim that immortalizing cells via hTERT bypasses cellular senescence while allowing epigenetic age to continue increasing with subsequent passaging is supported by published research on DNA methylation clocks. Development and benchmarking of the multi-tissue epigenetic clock demonstrated that DNA methylation age correlates directly with cell passage number in cultured cells, confirming that telomerase-mediated senescence bypass does not halt epigenetic aging during cell culture.

0:31:36Rhonda Patrick (host)supportedmoderate

Head and neck cancer patients treated with chemo-radiotherapy experienced an immediate 4.9-year acceleration in epigenetic age that normalized back to baseline after six to twelve months.

"these patients that had head and neck cancer, and they were getting treated for it—radiotherapy, chemotherapy—which causes massive damage, inflammation. These patients, their epigenetic age was measured before the treatment, after the treatment, and then six months later and a year later. And it was so interesting to me because they had aged—like their epigenetic age had accelerated by 4.9 years right after the treatment, but then six months later and a year later, their epigenetic age had normalized back to baseline." (said at 0:31:36)

A longitudinal study of 133 head and neck cancer patients receiving radiotherapy (most with concurrent chemoradiation) tracked epigenetic age using the Levine PhenoAge clock before treatment, immediately after treatment completion, and at 6 and 12 months post-treatment. Epigenetic age acceleration peaked immediately after radiotherapy with a 4.9-year increase compared to pre-treatment levels, before declining over subsequent follow-ups.

0:33:03Rhonda Patrick (host)supportedlow

Epigenetic age acceleration following cancer treatment correlated with inflammatory biomarkers, and patients with high inflammatory biomarkers at one year sustained epigenetic age acceleration.

"subanalysis then showed actually not only did the epigenetic age acceleration of almost five years correlate with inflammatory biomarkers, but people that had extremely high inflammatory biomarkers one year later did still experience the age acceleration." (said at 0:33:03)

In a prospective longitudinal cohort study of 133 patients with head and neck cancer undergoing radiotherapy (PMID 34027995), epigenetic age acceleration (EAA, measured via the Levine DNAmPhenoAge clock) increased by an average of 4.9 years immediately post-radiotherapy. Over time and at 1-year follow-up, higher levels of inflammatory markers (C-reactive protein and interleukin-6) were significantly associated with elevated and sustained epigenetic age acceleration (increases of 4.6 and 5.9 years in EAA for high CRP and IL-6 groups, respectively). Because this is an observational cohort study, the GRADE certainty is rated as low.

0:34:55Morgan Levinesupportedmoderate

The Hannum epigenetic clock incorporates blood cell composition measures, enabling it to capture inflammation signals more effectively than the original Horvath pan-tissue clock.

"Steve kind of called them intrinsic, extrinsic aging. I think he called the original Horvath pan-tissue clock the intrinsic aging. It wasn't that tuned to differences in kind of cell turnover or inflammation, whereas a clock that was developed by Hannum et al., he kind of added these different kind of cell composition measures that actually ended up picking up inflammation a little bit better." (said at 0:34:55)

The speaker accurately describes the concepts of intrinsic epigenetic age acceleration (IEAA) and extrinsic epigenetic age acceleration (EEAA) defined by Steve Horvath and colleagues. The original Horvath pan-tissue clock was used to derive IEAA by adjusting for blood cell proportions to capture cell-intrinsic aging independent of leukocyte turnover. In contrast, EEAA was constructed using the Hannum blood-based epigenetic clock combined with weighted measures of immune cell composition (such as naive and exhausted CD8+ T cells and plasmablasts) to capture immune cell composition shifts, turnover, and immunosenescence.

0:35:37Morgan Levinesupportedmoderate

Patients with severe COVID-19 exhibit a significantly more accelerated inflammatory epigenetic clock compared to asymptomatic or mildly symptomatic patients.

"Preliminarily, I can say we have data from individuals with COVID, and we can look at the inflammation measure, and we find that people with severe symptoms have much more accelerated inflammation epigenetic clock than people with basically asymptomatic or mild symptoms." (said at 0:35:37)

The claim that severe COVID-19 patients exhibit significantly more accelerated epigenetic aging compared to asymptomatic or mildly symptomatic individuals is supported by published observational studies measuring blood DNA methylation and epigenetic clocks across disease severities. A cohort study analyzing DNA methylation profiles from 413 COVID-19 patients and 232 healthy controls demonstrated progressive acceleration of epigenetic biological age corresponding to disease severity, with severe cases displaying significantly higher epigenetic age acceleration than non-severe cases.

0:43:23Morgan Levinesupportedhigh

Expressing the four Yamanaka factors (OSKM) converts adult somatic cells into induced pluripotent stem cells and resets their epigenetic age back to near zero.

"Yamanaka, who discovered what we call these Yamanaka factors, which are four transcription factors—we just call them OSKM—which when expressed, you can actually take a somatic, so an adult cell, and convert it back into what looks like an embryonic stem cell... not only are you making it embryonic-like in terms of its stem cell properties, but the epigenetic clocks seem to be almost completely reversed... you can take a skin cell that has an epigenetic age of 40 and do this—it takes, you know, a few weeks to do—and basically get back to an epigenetic age of zero in those cells." (said at 0:43:23)

Reprogramming adult somatic cells (such as dermal fibroblasts) into induced pluripotent stem cells (iPSCs) using the four Yamanaka transcription factors (OCT3/4, SOX2, KLF4, and c-MYC, or OSKM) resets their cellular phenotype to an embryonic-like state. Epigenetic clock analyses across human tissues demonstrate that DNA methylation age is effectively reset to near zero in both embryonic stem cells and fully reprogrammed iPSCs.

0:44:28Morgan Levinesupportedlow

During cellular reprogramming, epigenetic age reversal occurs before the cell loses its differentiated identity.

"partial reprogramming: so can we push the cell back a little bit? Because actually what we find is that this age reversal happens first, prior to the cell losing its identity." (said at 0:44:28)

Preclinical in vitro studies show that transient or partial expression of Yamanaka reprogramming factors can uncouple rejuvenation from full dedifferentiation. Epigenetic age clocks and transcriptomic aging signatures can be substantially reset during the early-to-intermediate stages of reprogramming before somatic cells permanently lose their differentiated identity.

0:45:07Rhonda Patrick (host)supportedvery low

Partial cellular reprogramming in progeria mouse models reverses hallmarks of aging and extends healthspan.

"with some of the recent work at least out of his lab, they're using a premature aging mouse model, a progeria model, and have shown—I know there's a new publication I haven't read that just came out; the older one, the first one, 2016 or something Cell paper, I remember they showed in multiple different organs it seemed to reverse some of the hallmarks of aging, you know, and the organs were performing functionally a little bit younger than you would imagine. And at least in this premature aging mouse model—and I think even healthspan of this mouse model that's prematurely aging, it seemed to be improved." (said at 0:45:07)

The speaker accurately describes the findings of the landmark 2016 study by Ocampo et al. published in Cell. In that study, the researchers demonstrated that cyclic, in vivo expression of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) induced partial cellular reprogramming, ameliorating cellular and physiological hallmarks of aging and extending lifespan in a transgenic mouse model of Hutchinson-Gilford progeria syndrome (LAKI mice). Because the evidence is derived exclusively from animal models, certainty is rated as very low regarding applicability to humans.

0:46:12Morgan Levinesupportedvery low

Partial cellular reprogramming in wild-type mice and in cultured cells reverses epigenetic age and improves cellular function.

"the new publication, which is done in more of a wild-type, not a progeroid mice, now does show kind of some reversal of the epigenetic clock. And you can do this just cells in a dish: we can partially reprogram them and show reversal of epigenetic clock and other functional improvements in the cells." (said at 0:46:12)

The claim accurately reflects findings from preclinical research. In wild-type mice undergoing physiological aging, in vivo partial reprogramming (using cyclic induction of Yamanaka factors Oct4, Sox2, Klf4, and c-Myc) was shown to reverse the DNA methylation epigenetic clock across multiple tissues and reduce markers of inflammation and senescence. Similarly, transient or partial reprogramming in cultured cells in vitro (both in human dermal fibroblasts and mouse cells) has been demonstrated to substantially reduce epigenetic age while restoring youthful cellular functions, such as improved cellular respiration, increased collagen production, and restored migration speed. Because the evidence is derived entirely from animal models and in vitro cell culture, certainty is rated as very low.

0:47:58Morgan Levinesupportedlow

Cellular reprogramming resets damaged mitochondria back to a younger, better-functioning state.

"The exciting thing is actually the mitochondria seems to also be kind of rejuvenated. If—I mean, I don't really like that term rejuvenated, but it seems to be kind of set back to a better-functioning state." (said at 0:47:58)

Cellular reprogramming (via induced pluripotency or partial reprogramming using Yamanaka factors) has been shown in pre-clinical cellular models to restore youthful mitochondrial morphology, decrease oxidative stress, and reset metabolic and respiratory function back toward a youthful state.

0:50:20Morgan Levinesupportedvery low

Heterochronic parabiosis accelerates aging in young mice and rejuvenates old mice.

"they'll do what's called heterochronic, where they take one young mouse and one old mouse and connect them and then just say, "What happens to the aging? The young mouse that, you know, is now having some influence from the old mouse and vice versa?" And what we find is that the young mice has accelerated aging compared to one that's paired with another young mouse, and the old mouse is somewhat rejuvenated compared to an old mouse compared to an old mouse." (said at 0:50:20)

Heterochronic parabiosis—surgically conjoining the circulatory systems of a young mouse and an old mouse—has consistently demonstrated in preclinical rodent models that systemic factors in old circulation impair stem cell function and promote aging-like phenotypes in young mice, while exposure to young circulation partially restores progenitor cell proliferation and tissue regeneration (rejuvenation) in old mice compared to isochronic pairs. Evidence is limited to animal models.

0:51:10Morgan Levinesupportedlow

Culturing fetal cells in serum from older individuals causes the cells to age in vitro compared to culturing them in young serum.

"We actually buy serum from older individuals versus younger individuals, and we can grow our cells in these two different conditions. And we, again, can age even fetal cells using old serum versus the young serum seems to be not as problematic." (said at 0:51:10)

In vitro studies evaluating heterochronic serum exposure confirm that culturing young or fetal human cells in serum derived from older donors induces markers of cellular aging and senescence (such as senescence-associated beta-galactosidase activity, DNA damage markers, and increased epigenetic age clocks) compared to culturing in young human serum. Because evidence is limited to in vitro experimental cell models, certainty for broader systemic applications remains low.

0:51:25Rhonda Patrick (host)supportedvery low

Diluting old plasma with saline and albumin rejuvenates old mice without showing any significant effect in young mice.

"recent work out of Irina Conboy's lab at UC Berkeley. What was interesting to me about her research—or her recent research—was that they were able to take this plasma and, basically it was just saline and albumin, right? And then they took old mice and it was essentially diluting out their old plasma, and it rejuvenated these mice. Whereas they did it with the young mice, there's really no effect." (said at 0:51:25)

A 2020 study from Irina Conboy's laboratory at UC Berkeley (Mehdipour et al.) demonstrated that 'neutral' blood exchange (NBE)—replacing half of the blood plasma in old mice with a physiological solution of saline and 5% albumin—diluted age-elevated plasma factors and led to multi-tissue rejuvenation, enhancing muscle repair, reducing liver fibrosis and adiposity, and increasing hippocampal neurogenesis. In young mice, control experiments showed that the procedure did not alter normal baseline regenerative parameters or produce the rejuvenating effects seen in old mice. Because the claim is supported exclusively by animal experimental data, the certainty of evidence is rated very low.

  • supports: Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-album… (Aging 2020) · cited 117x in the literature
    "Here, using our recently developed small animal blood exchange process, we replaced half of the plasma in mice with saline containing 5% albumin (terming it a "neutral" age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity." (abstract, passage verified)
    pubmedfull study (doi)
0:52:26Morgan Levinesupportedvery low

Heterochronic parabiosis alters the epigenetic clock in mice.

"in the normal kind of parabiosis context, it does change the epigenetic clock." (said at 0:52:26)

Animal studies demonstrate that heterochronic parabiosis alters DNA methylation-based epigenetic clocks in mice in both directions: exposure to young circulation significantly reduces the epigenetic age of tissues (such as blood and liver) in aged mice, while pairing young mice with aged partners increases their biological and epigenetic age.

0:56:02Rhonda Patrick (host)supportedmoderate

Exercise is associated with a slowing of epigenetic aging.

"exercise is also associated with the slowing of epigenetic age." (said at 0:56:02)

A systematic review and meta-analysis of 44 studies comprising 145,465 participants confirmed that higher physical activity is significantly associated with lower biological age and reduced epigenetic age acceleration (EAA), specifically for Horvath EAA and GrimAge EAA. Because the body of evidence consists primarily of cross-sectional and prospective observational cohort studies, it directly supports the host's claim of an association.

0:56:06Morgan Levinesupportedmoderate

Genetics accounts for only 10% to 20% of the variance in human epigenetic aging and lifespan.

"you were saying genetics, it seems as though there's 10 to 20%, you mentioned. GUEST1: Yeah, it's pretty small. Pretty small in terms of epigenetic aging. But even in terms of lifespan, it seems to be on par with that. So only a small percentage of the way you age is controlled by genetics." (said at 0:56:06)

Large-scale genetic and pedigree studies support the estimate that genetics accounts for a relatively small proportion of the variance in human lifespan and epigenetic aging, generally estimated around 10% to 20% (or even less). In a large-scale pedigree analysis of over 400 million individuals, historical lifespan heritability was traditionally estimated between 15% and 30%, and fell below 10% after adjusting for assortative mating. Similarly, comprehensive family and twin modeling across the lifespan indicates that environmental and cohabitation factors explain the vast majority of variation in DNA methylation age, with genetic factors accounting for approximately 13% of the variance.

0:57:12Morgan Levinesupportedmoderate

Supercentenarians do not smoke less, eat better, or exercise more on average than the general public.

"These supercentenarians don't necessarily smoke less or eat better or exercise more than people in the general public, but they're somehow able to overcome that and survive to extreme ages." (said at 0:57:12)

A landmark study examining 477 Ashkenazi Jewish individuals with exceptional longevity (aged 95 to 109 years) compared their lifestyle habits with a birth-cohort-matched general population sample from the National Health and Nutrition Examination Survey (NHANES I). The study found no significant differences in body mass index, dietary caloric restriction, frequency of regular physical activity, or alcohol consumption between the long-lived individuals and the general public, supporting the speaker's claim that individuals reaching extreme old age do not necessarily engage in healthier lifestyle behaviors than average.

0:58:02Morgan Levinesupportedhigh

Smoking decreases human life expectancy by approximately 10 years.

"smoking decreases people's life expectancy by about 10 years, but you have these people who survive to 100 or beyond still smoking." (said at 0:58:02)

Large prospective cohort studies consistently demonstrate that continuing cigarette smokers lose approximately 10 years (or at least one decade) of life expectancy compared with lifelong non-smokers. In the British Doctors Study (50-year follow-up of 34,439 men), persistent cigarette smokers died on average about 10 years younger than lifelong non-smokers. Similarly, an analysis of over 200,000 U.S. adults from the National Health Interview Survey found that current smokers shortened their life expectancy by more than 10 years compared with never-smokers.

0:58:33Rhonda Patrick (host)supportedlow

In a Japanese cohort study of centenarians and supercentenarians, low levels of inflammation was the sole biomarker category that predicted survival into higher extreme age brackets.

"they looked at elderly, and then they looked at going from elderly to a centenarian, from centenarian to a semi-supercentenarian, which is 105, and then to a supercentenarian, which is like 110. And they looked at a whole battery of biomarkers. I don't think epigenetic clock was in there, but they looked at telomere length, immunosenescence, all the blood work stuff, metabolic and lipids and stuff. And then they looked at inflammatory biomarkers. And it was funny—it was interesting because the suppression of inflammation was the only thing that could predict going to the next age group, or surviving to" (said at 0:58:33)

In a 2015 longitudinal study combining three Japanese cohorts of very old individuals, centenarians, and (semi-)supercentenarians (TOOTH, TCS, and JSS cohorts; n = 1,554), researchers evaluated multiple biomarker domains, including inflammation, haematopoiesis, lipid and glucose metabolism, liver function, renal function, and cellular senescence/telomere length. Low inflammation was the only domain among those tested that consistently predicted all-cause mortality and cognitive/physical capability across extreme age groups, whereas other markers, such as telomere length, did not predict survival in semi-supercentenarians.

  • supports: Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Lo… (EBioMedicine 2015) · cited 332x in the literature
    "We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender." (abstract, results, passage verified)
    pubmedfull study (doi)
0:59:34Rhonda Patrick (host)supportedhigh

The Omega-3 Index measures omega-3 fatty acid levels in red blood cell membranes as a long-term marker of omega-3 status rather than acute dietary intake.

"He does a lot of work using the omega-3 index, which he co-developed, where they measure omega-3 in red blood cells. It's a long-term marker of omega-3 rather than like what you had the night before" (said at 0:59:34)

The claim is supported by clinical and laboratory literature. The Omega-3 Index, co-developed by William S. Harris and Clemens von Schacky, measures the proportion of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in red blood cell (RBC) membranes. Because red blood cells have a lifespan of approximately 120 days, RBC fatty acid composition reflects long-term dietary intake and tissue status of EPA and DHA rather than acute short-term fluctuations or recent dietary intake.

1:00:05Rhonda Patrick (host)supportedmoderate

The typical American diet results in an omega-3 index of about 4%, compared to Japan where the average is 10% or higher.

"typical American diet is they have about a 4% omega-3 index, and that's kind of low, especially if you compare it to other countries like Japan where their average omega-3 index is like 10% or much higher." (said at 1:00:05)

The speaker's statement accurately reflects published global and cross-national surveys of blood omega-3 levels. A systematic global review of 298 studies (Stark et al., 2016) found that typical blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in North America fall into the very low range (≤4% erythrocyte equivalents), whereas populations around the Sea of Japan and parts of Scandinavia have high levels (>8% to >10%). Similarly, multi-country comparisons using standardized red blood cell measurements (Harris et al., 2022) found typical US cohorts had low mean Omega-3 Index levels, while Japanese cohorts fell into the desirable range (>8-10%).

1:00:36Rhonda Patrick (host)supportedlow

In Framingham data, individuals with an 8% omega-3 index had a five-year increased life expectancy compared to those with a 4% omega-3 index.

"people with an 8% omega-3 index had a five-year increased life expectancy compared to people with the 4% omega-3 index." (said at 1:00:36)

The claim accurately describes findings derived from prospective analyses of the Framingham Offspring Cohort. In this cohort, baseline red blood cell omega-3 index (O3I) was strongly and inversely associated with all-cause mortality, with modeling showing that individuals with an optimal omega-3 index (~8%) had an estimated 4.7 to 5 additional years of life expectancy compared to those with a low index (~4%), an effect size comparable in magnitude to the mortality risk associated with smoking. Because these data come from observational cohort analyses rather than randomized controlled trials, certainty is rated low.

1:04:39Morgan Levinesupportedhigh

Running the same split blood sample twice on original epigenetic clocks can produce differences of up to eight years in estimated epigenetic age.

"we've taken blood samples, you can split them, like the same sample run it twice, and you can get upwards of eight years difference in your epigenetic age using traditional clocks." (said at 1:04:39)

Published technical evaluations of traditional epigenetic clocks show that technical variation between replicate split samples from the same biological source can produce discrepancies of up to 8 to 9 years in estimated epigenetic age. Higgins-Chen and colleagues (2022) systematically evaluated six prominent original epigenetic clocks and demonstrated that technical noise causes replicate deviations of up to 9 years, leading to the development of principal-component-based clock variants to resolve this reliability issue.

1:06:41Morgan Levinesupportedhigh

First-generation epigenetic clocks trained to predict chronological age are less predictive of mortality risk after adjusting for chronological age than second-generation clocks like GrimAge or PhenoAge.

"And people who are using these first-generation clocks, the ones trained to predict chronological age, are not as good at that. So yes, there's a lot of tests on the market, but I think it's really important to make sure you're using ones trained more like the second-generation clocks, so things like GrimAge or PhenoAge" (said at 1:06:41)

Large-scale prospective cohort studies consistently demonstrate that second-generation epigenetic clocks (such as DNAm GrimAge and DNAm PhenoAge), which were trained on clinical biomarkers, physiological traits, or mortality risk, significantly outperform first-generation clocks trained strictly to predict chronological age (such as the Horvath and Hannum clocks) in predicting time-to-death and age-related health outcomes after adjusting for chronological age.

1:08:43Rhonda Patrick (host)supportedlow

A study by Kara Fitzgerald and colleagues reported a reversal in epigenetic age of approximately three years following a multi-modal dietary and lifestyle intervention.

"So there was a very, very small study—extremely small study—published by a gal that reached out to me, her name was Kara Fitzgerald, and she and her colleagues had taken a small sample of people and they underwent like an extreme dietary change... And this was like a I think it was pretty short treatment... But their epigenetic age, according to the clock they used... had reversed by like three years or something." (said at 1:08:43)

A 2021 pilot randomized controlled trial by Kara Fitzgerald and colleagues evaluated an 8-week multimodal diet and lifestyle intervention (including dietary adjustments, sleep, exercise, relaxation guidance, and supplements) among 43 healthy men aged 50–72. Using the Horvath DNAmAge clock, participants in the treatment group showed a 3.23-year decrease in epigenetic age compared to the control group (p = 0.018), and a within-group decrease of 1.96 years (p = 0.066). The host accurately described the study's small sample size, short duration, and reported ~3-year epigenetic age reduction.

  • supports: Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot rand… (Aging 2021) · cited 372x in the literature
    "Herein we report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72. The 8-week treatment program included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients. The control group received no intervention. Genome-wide DNA methylation analysis was conducted on saliva samples using the Illumina Methylation Epic Array and DNAmAge was calculated using the online Horvath DNAmAge clock (2013). The diet and lifestyle treatment was associated with a 3.23 years decrease in DNAmAge compared with controls (p=0.018)." (abstract, results, passage verified)
    pubmedfull study (doi)
1:09:43Morgan Levinesupportedmoderate

Re-analysis of Kara Fitzgerald's intervention dataset using statistical noise-removal methods showed that the observed reversal in epigenetic age was entirely attributable to technical noise.

"And we were actually able to go back in and show that the entire effect was noise. So actually, once you do the statistical method that removes the noise, there was actually no effect of the intervention." (said at 1:09:43)

Re-analysis of intervention trials (such as the diet and lifestyle intervention published by Fitzgerald et al.) using principal-component (PC) and reliability-adjusted epigenetic clock methods developed to remove technical noise (Higgins-Chen et al., Nature Aging 2022) demonstrated that original chronological-age clocks (e.g., standard Horvath DNAmAge) suffered from substantial technical noise (up to 9 years of deviation between replicates). When noise-reduced PC clocks or high-reliability metrics were applied, the apparent dramatic age reversals reported in small intervention datasets disappeared or were revealed to be false-positive statistical artifacts.

1:15:20Rhonda Patrick (host)supportedmoderate

In a two-year human caloric restriction study (the CALERIE study) from Yale, caloric restriction slowed thymic aging.

"so did you see that paper that came out of Yale from Vishwa—like I didn't in depth read it, I just sort of glanced at it, but there was a two-year caloric restriction— Yeah, yeah, that's from the CALERIE study, yeah. so and thymic aging was like slowed which was kind of" (said at 1:15:20)

In a 2-year randomized clinical trial of calorie restriction in healthy non-obese humans (the CALERIE trial, analyzed by Vishwa Deep Dixit's team at Yale), participants randomized to ~14% caloric restriction demonstrated increased functional thymus volume on MRI, improved thymopoiesis (new T-cell production), and mobilization of ectopic lipid from the thymus, indicating a rejuvenation or slowing of age-related thymic involution.

1:17:25Morgan Levinesupportedvery low

Caloric restriction substantially slows epigenetic aging in mice, with longer duration producing progressively slower accumulation of epigenetic age.

"So in mice epigenetic age is affected by calorie restriction and substantially slowed, and the longer the animals are on it, the kind of slower the increase in epigenetic age over time becomes." (said at 1:17:25)

Preclinical studies using DNA methylation clocks in mice demonstrate that caloric restriction significantly slows the rate of biological/epigenetic aging compared to ad libitum fed controls. Because these findings are established entirely in animal models, the GRADE certainty is graded as very low.

1:17:45Morgan Levinesupportedmoderate

Studies in rodents show that different genetic backgrounds respond differently to caloric restriction, and some mouse strains experience worse health or lifespan outcomes.

"And there are studies in rodents showing that different genetic backgrounds have different responses, some actually do worse with caloric restriction." (said at 1:17:45)

Controlled rodent experiments demonstrate substantial genetic variation in the response to dietary and caloric restriction. In an unbiased screen of 41 recombinant inbred mouse strains subjected to 40% caloric restriction, lifespan responses varied widely from life extension to significant life shortening across different genetic backgrounds, with dietary restriction shortening lifespan in more strains than those in which it extended life. Subsequent metabolic evaluations also confirmed strain-dependent divergences in adiposity, metabolomic profiles, and health outcomes under caloric restriction.

1:18:05Morgan Levinesupportedvery low

Rodent studies show that the longevity benefits of caloric restriction are lost when the restriction is discontinued.

"there's studies, even in mice, that if you stop it, you lose the benefit." (said at 1:18:05)

Rodent studies examining dietary and caloric restriction (CR) have shown that the mortality and longevity benefits are acute and largely reversible upon discontinuation. In large-scale mouse nutritional switch experiments, animals maintained on dietary restriction that were returned to ad libitum feeding experienced an acute increase in mortality, losing the survival advantages conferred by restriction. Because this evidence is derived from animal models, the GRADE certainty is very low.

4

No source found (not proven false)

0:24:05Morgan Levineunverifiedvery low

Epigenetic clock methylation changes occur most rapidly during development, become steady around age 20, and slow down after age 80.

"The epigenetic clocks show a totally different pattern: it's still not linear, but actually most of the changes happen during development. So you have this huge increase in epigenetic age between—we can even measure it in fetal samples—and then it kind of starts becoming more linear and steady around age 20. And then interestingly, it actually slows down again in very late life, so after let's say age 80." (said at 0:24:05)

No published record matching the claim that epigenetic clock methylation changes occur most rapidly during development, stabilize around age 20, and slow down after age 80 was located; this does not prove the claim false.

0:25:30Morgan Levineunverifiedvery low

Developing a chronic disease is associated with a shortened time interval to developing subsequent chronic diseases.

"And we do know, not looking at epigenetics, that once you get a disease, it's actually shorter time to each subsequent disease." (said at 0:25:30)

No published record matching the claim that developing a chronic disease is associated with a shortened time interval to each subsequent disease was located; this does not prove the claim false.

1:01:57Rhonda Patrick (host)unverifiedvery low

A six-month trial of 5 grams per day of EPA/DHA fish oil in women genetically predisposed to breast cancer showed hypomethylation in inflammatory pathways such as TNF-alpha in PBMCs.

"The study was women that were genetically predisposed to breast cancer, they were given five grams a day of fish oil, so it was EPA/DHA omega-3, the marine omega-3 fatty acids, and this was like six months treatment. And they had done some sort of methylation profiling—not epigenetic clock, but profiling of their PBMCs, their peripheral blood mononuclear cells, and there was like hypomethylation in I think it was like TNF-alpha or some one of the major controllers of inflammation where it was decreasing inflammation." (said at 1:01:57)

No published record matching a six-month trial of 5 grams per day of EPA/DHA fish oil measuring PBMC DNA methylation in women genetically predisposed to breast cancer was located; this does not prove the claim false.

1:14:08Morgan Levineunverifiedvery low

Exercise has been shown to reverse diabetes better than metformin.

"Or they've even shown you can reverse diabetes through exercise or any of these things better than metformin." (said at 1:14:08)

No published record matching the claim that exercise reverses diabetes better than metformin was located; this does not prove the claim false. While landmark clinical trials such as the Diabetes Prevention Program demonstrated that intensive lifestyle interventions (combining diet and physical activity) were more effective than metformin at preventing or delaying the onset of type 2 diabetes in individuals with prediabetes, these findings pertain to diabetes prevention rather than the reversal or remission of established type 2 diabetes.

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.