HoldsUp

Morgan Levine

Altos Labs / Yale University School of Medicine

Morgan Levine, PhD, is an assistant professor of pathology at the Yale University School of Medicine and a Founding Principal Investigator at Altos Labs. Her research centers on the science of biological aging, epigenetics, and the development of aging metrics such as the PhenoAge clock. Her published work investigates epigenetic age acceleration, blood methylation tests across physiological systems, mitochondrial function, and the effects of lifestyle interventions on biological age.

37 claims checked on air: 1 contradicted 1 overstated 32 supported 3 unverified

What they said on air

6 citing their own research

0:07:39supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:08:00supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:10:42supportedhightheir own paperMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:11:35supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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).

0:15:44supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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).

0:15:55supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:20:38contradictedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:21:15supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:21:29supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:22:26supportedmoderatetheir own paperMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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).

0:23:00supportedmoderatetheir own paperMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:23:58supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:24:05unverifiedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:25:30unverifiedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:28:45supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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).

0:29:10supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:30:01supportedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:34:55supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:35:37supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:43:23supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:44:28supportedlowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:46:12supportedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:47:58supportedlowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:50:20supportedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:51:10supportedlowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:52:26supportedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:56:06supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:57:12supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

0:58:02supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:04:39supportedhightheir own paperMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:05:09overstatedmoderatetheir own paperMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:06:41supportedhighMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:09:43supportedmoderatetheir own paperMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:14:08unverifiedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:17:25supportedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:17:45supportedmoderateMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

1:18:05supportedvery lowMorgan Levine, PhD, on PhenoAge and the Epigenetics of Age A

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.

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