"Factors Influencing Longevity and Healthspan: Genetics, Hormones, Lifestyle, Environment"

Genetics 1:51 0
“if my interpretation of the literature is is at least partially correct it appears that genes play a significant role so genes don't seem to play a big role in people living to 70 versus 80 but boy when you start to talk about living to 90 versus 100 you know relative to 70 or 80. genes play a pretty big role”

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Genetics 2:24 0
“my grandfather got a heart attack when he was 68 and he died that's my grandfather my father got a heart attack at 68 and he had triple bypass and he died at 84. so the correlation between age of death in different cohorts is not much revealing”

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Genetics 3:52 0
“twins are usually born small for their gestational age in fact it's more true that one of the twins is small for their gestational age”

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Genetics 5:08 0
“we know that twins or the people that the babies that are born small for age develop age-related disease very rapidly it's called the barker hypothesis”

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Genetics 7:07 0
“the second hypothesis is that they have perfect genome you know we we know that we have a lot of genotypes that are putting us at risk for variety of age-related disease so maybe one out of ten thousand doesn't have that and that's why they're flying in so gracefully.”

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Genetics 8:00 0
“we took our first 44 centenarians and did the whole genome sequencing at the time huge expense but we only had those centenarians okay we don't have had a control but we had a great instrument we thought it's called clinvar it's an accumulation of all the genes that have shown to be causing diseases.”

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Genetics 9:26 0
“each centenarian had between five and six bed variants five and six out of fifteen 000 possible right and we didn't have a control so we don't know how many the average person had right but but think of it those centenarians each one have had five variants that will probably cause a disease and none of them had it.”

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Genetics 13:56 0
“then there are very likely to be longevity genotypes”

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Genetics 14:17 0
“if we have if we make a good drug okay if the drug is really good it targets exactly that without side effects”

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Genetics 14:36 0
“the suppression of the expression of those genes”

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Genetics 16:39 0
“look for phenotypes that are different and work backwards to find genotypes”

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Genetics 19:24 0
“those centenarians were born with clutter but they were also born with longevity genes which made the the clutter not significant”

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Genetics 20:41 0
“it became apparent that you change just one gene in a nematode and they can leave ten times longer right by the way the gene was bugging me because it's the insulin receptor or the igf insulin receptor gene and the nematodes were insulin resistant and they also had abdominal obesity they accumulated fat in their intestinal cell”

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Genetics 21:52 0
“60 of our centenarians have genes that impairs growth hormone igf singling pathway including the foxo3a”

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Genetics 25:39 0
“we discovered that our centenarians have deletion of exon 3 in the growth hormone receptor”

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Genetics 30:14 0
“we recently published a paper because we didn't understand so well why the literature is called so confusing us with the growth from an igf we went to the uk biobank which has really changed our ability to validate and to learn and to get hypotheses and they have 440 000 people who have actually igf-1 measurements”

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Genetics 30:46 0
“for young people high igf-1 was protective from variety of age age-related diseases and from mortality although not from cancer”

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Genetics 31:25 0
“people over the age of 60 it's exactly the opposite, they had more of every age-related disease except cancer and they also had increase in mortality”

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Hormone balance 35:40 0
“it's a hormone that that i've prescribed to patients when they're healing from injuries so i've seen pretty good literature that says you know you tear a bicep you have surgery to repair it growth hormone for eight weeks fosters rehabilitation better than if you did nothing.”

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Hormone balance 36:48 0
“i've drawn a hard line in the sand with my patients that i don't believe in the literature that would suggest that prescribing growth hormone is a pro-longevity tool but if i'm being brutally honest and i tell them this as well i can't tell you that it's killing you either.”

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Hormone balance 39:05 0
“it is possible that things that you're doing are good for you when you're young and against you when you're old.”

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Hormone balance 42:03 0
“those with the lowest half of igf-1 lived twice as long as those with the highest level of igf-1”

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Cognitive stimulation 42:55 0
“those women also have better cognitive function”

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Genetics 44:41 0
“centenarians are more likely to have apoe2 than non-centenarians which is the protective variant of that gene”

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Genetics 48:48 0
“they are protected by other longevity gene and it makes it irrelevant what is lp like although i don't think those are mutually exclusive i think the former is an explanation apparently i think that the latter is an explanation for the former it's the amplifier of it right it's what lets them get there in the first place is that using ctep as an example they happen to have a ctep mutation or a ctep variant that offers remarkable protection against atherosclerosis of which an interesting but kind of irrelevant phenotype is high hdl cholesterol and that's offsetting the damage of their lp little a and then eventually at some point when everybody else has died because of their lp little a they're still standing and they might even be getting some benefit from lp little a that everybody gets but it's in other people's cases it's so dwarfed by the damage of lp little a again total hypothesis or speculation but that it's a it's a it's plausible right it is”

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Hormone balance 50:07 0
“the thyroid story is interesting because we found a correlation between high tsh and longevity and when when i say as an endocrinologist near maybe give people the the two-minute story on what tsh is and how it functions you know i i promise to some of my you know my my sisters are listening to you and i promised i'm going to be so simple you won't need to call me again and ask me what did you mean and now i'm falling into it i know i i do i'm doing a bad job of this i'm sorry you're absolutely right so uh tsh is really the your control of thyroid function in the sense that if you become hypothyroid then this tsh this hormone from the pituitary will increase in order to get those thyroid hormones to be normal again and they might fail and then you'll be hypothyroid but there's an effort to get those thyroid out of your glands okay so that's tsa so when we see a high tsh in a normal person we ask the first question is their thyroid gland not making enough t4 and or converting enough of that t4 to…”

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Metabolic health 55:43 0
“that their metabolism is maybe slow and although they're compensating by higher tsh still their metabolism you know it's like insulin resistant you don't totally normalize the glucose although you have enough insulin for that that there's a metabolic over of metabolic advantages”

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Genetics 57:08 0
“we have lots of genotype and we try to integrate those genotypes in order to assess how much they are increasing the risk of us of getting a disease and usually it's not by much”

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Genetics 59:39 0
“the genetics of longevity in humans is exactly what we learned from animals it's the insulin signaling pathway, it's the mtor signaling pathway, it's the map kinase pathway”

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Genetics 1:02:45 0
“we're starting to look at other genes that are abrogating some of the effects of this and so now the focus has been less at looking at apoe4 and making a determination and it's looking at e4 plus tom 40 plus mitochondrial haplotype plus clotho plus a whole bunch of genes and taking a polygenic approach to risk”

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Genetics 1:03:35 0
“in looking for those longevity genes that we just published 12 of them are associated with resiliency to Alzheimer's and I think that not enough of the genetics is explaining not only the genetics but the resiliency or looking at the genetics of resiliency which is what we're calling longevity in this case but the resiliency to diseases which happens to diseases that you get in young age too”

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Genetics 1:04:54 0
“we have 750 centenarians in our study now they are all Ashkenazi Jews and there are Ashkenazi Jews why is that not because religious is important but because Ashkenazi Jews are a genetically homogeneous they went through a bottleneck an expansion and then a bottleneck and very few survived and they lived in isolation and intermarriage and their genetic pool is much more homogeneous”

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Genetics 1:09:53 0
“and even if you identified which genes played a role the likelihood that you'll identify which environmental factors turned on those genes or amplified some and attenuated others seems very low”

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Environment 1:12:40 0
“how much can environment hurt or better what is already a genetic lottery”

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Exercise 1:13:32 0
“we're doing with exercise and and and food”

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Nutrition 1:13:32 0
“we're doing with exercise and and and food”

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Disease prevention 1:16:36 0
“at the age of 100, 30% don't have a disease and are not treated with anything but they have such a compression of morbidity they are sick for months at the end of their life unlike us that are sick for years at the end of our lives.”

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Disease prevention 1:17:59 0
“the centenarian has their first heart attack at 101 and you know they die six months later.”

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Disease prevention 1:20:50 0
“if you prevent aging and age-related disease you're going to compress morbidity too.”

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Disease prevention 1:24:23 0
“if we can prevent diseases that's their measurements right”

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Economic impact 1:25:43 0
“if you increase the health span of someone it's not only medical costs because this guy is going to travel and spend money traveling and buy gadgets and buy houses for his kids”

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Social connection 1:28:42 0
“my centenarians have to have offspring”

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Purpose 1:32:41 0
“it's a way to remind everyone myself included that we're not that important like no matter i mean like my point being is my great-grandchildren will never know who i am”

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Social connection 1:33:14 0
“these centenarians have a gift right which is their great grandchildren will know them and when you use this example when you can go to concerts with your great grandchildren that's amazing when you could take a vacation with your great grandchild”

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Exercise 1:34:15 0
“the lesson for most of us is still right exercise and nutrition whatever it means to everyone and everything else that you give right that's that's the lesson and it's not the lesson from centenarians”

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Disease prevention 1:38:19 0
“nothing matters more than prevention of chronic disease”

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Substances 1:38:58 0
“i probably get an equal number of questions near about the following three things: metformin, rapamycin, or some combination of nr nad or nmn”

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Substances 1:42:09 0
“metformin is an extract of the french lilac so some people say it's nutraceutical it it is modified and it is a drug”

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Disease prevention 1:42:44 0
“metformin was used initially to treat the flu and malaria and inflammatory diseases”

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Disease prevention 1:45:15 0
“people start to notice that diabetics who take metformin when compared to diabetics who don't take metformin do better”

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Disease prevention 1:49:50 0
“for example there are two studies on people with mild cognitive impairment that were treated with metformin one for half a year and one for one year and some of the outcomes have changed and there is no different in how they were treated”

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Disease prevention 1:51:06 0
“we have to think in general science that aging is going to drive your next disease”

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Disease prevention 1:52:00 0
“the whole problem of the statistics obtain is to make sure that we're not getting to any significant in any disease just to trends”

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Disease prevention 1:56:02 0
“there are metformin studies which included elderly people for example the DPP... and their results were similar in prevention diabetes to younger people.”

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Disease prevention 1:57:00 0
“it suggests that if TAME shows a reduction in all-cause mortality in a subset of people so old, it would suggest biologically that there would be a benefit to starting sooner.”

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Disease prevention 1:58:12 0
“we would like to start longitudinal study where we capture a lot of the other health spin issues you know hospitalization and function and depression and all that.”

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Substances 2:02:15 0
“there are several other animals that live longer and healthier with metformin but i don't think that 0.1 is really the appropriate dose”

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Disease prevention 2:04:29 0
“the effects on health span is much but what are the health span effects besides the metabolic effects cancer prevention of cancers”

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Genetics 2:04:56 0
“the problem for us with animals is by the way it's the problem with centenarians also they die with cancers we don't know if they die”

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Genetics 2:09:35 0
“if you think of genetics only whole exome sequencing for 3,000 people or my proteomics which is 5,000 protein for a thousand people it's all big data”

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Genetics 2:10:03 0
“the first paper that came out of the UK Biobank for aging said that longevity is all about assortative mating.”

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Disease prevention 2:10:41 0
“what are the biomarkers for aging you know how can we do a test at 50 years old and know if we're 40 or we're 60. if we're 40 we skip colonoscopy okay if if we're 60 we have to do something about it already”

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Genetics 2:12:01 0
“a lot of the proteins that we're capturing by the way number one is IGF related proteins okay number one that comes up even in the proteomic not only in the genomics”

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Genetics 2:14:05 0
“the proteome of females is much more stable in other words it's only half of the proteins are significantly changing in women than in men between those ages”

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Metabolic health 2:16:42 0
“when fasting glucose and vitamin D level factor into a biologic clock I'm sorry that's useless.”

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Genetics 2:18:01 0
“you then looked at methylation clocks of them after a year and they were vastly different and then three days later after the twin brother was back on earth for three days they repeated the test and it was right back to his twin brother.”

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Genetics 2:20:09 0
“morgan levine has a mechanistic way of looking at epigenetics remind me what the inputs are to the levine clock.”

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Immunizations 2:23:18 0
“are you impacting immune function specifically memory t and b cell function”

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Exercise 2:24:46 0
“what about exercise function because one of the things i want to talk about before we leave metformin is the impact metformin may have as a negative impact on cardiorespiratory fitness”

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Metabolic health 2:27:01 0
“my fasting lactate level was typically above one millimole it was between one and two millimole”

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Exercise 2:28:03 0
“so now we have a couple of studies that have looked at the impact of metformin on cardiorespiratory fitness and we see that it is indeed impaired”

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Exercise 2:28:14 0
“and then we have studies that look at the impact on metformin of strength training and we see a mixed response we see that it does not appear to impact strength gains it only appears to impact hypertrophy”

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Exercise 2:28:27 0
“the good news is we know that strength matters more than hypertrophy in longevity”

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Exercise 2:35:36 0
“we took the biopsies and looked at the transcript of the people who were on exercise and metformin versus exercise only”

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Exercise 2:34:41 0
“but in others for example those who exercise a lot it might not be beneficial because they're getting so many of those other benefits of exercise as you point out”

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Exercise 2:35:42 0
“i can tell you that i'm with metformin and fasting my exercise capacity is increased significantly”

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Metabolic health 2:36:17 0
“i'm really reserving metformin only for people in whom i see an otherwise obvious indication such as even a trace of insulin resistance hyperinsulinemia”

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Gut health 2:41:04 0
“they go to the microbiome and the microbiome either transfer the nad or does something the microbiome itself does something you know there there's indirect health benefit from a dufferin system”

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Sleep 2:42:15 0
“i started taking nmn at one point and what i noticed is my rem sleep has improved a lot and i stopped it and my rem sleep wasn't so good i restarted it and my rem didn't get better again”

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Longevity emerges as a tapestry woven from genetics, hormones, lifestyle, and environment. Nobel insights from centenarian studies and large biobanks highlight how these factors intersect to determine not just lifespan, but healthspan—the years lived free of chronic disease.

Genetic Determinants
Genes exert minimal influence on reaching age 70 versus 80, but their impact surges when comparing those who live to 90 or 100. Whole-genome sequencing of 44 centenarians revealed each carried 5–6 potentially disease-causing variants yet remained disease-free, implying the existence of protective “longevity genotypes.” Key pathways mirror those in animal models—insulin/IGF signaling, mTOR, and MAP kinase—with variants in FOXO3a and growth-hormone/IGF-1 axis genes (e.g., exon 3 deletion in GHR) enriched among the oldest old. APOE2, the “protective” isoform of APOE, is overrepresented in centenarians, and polygenic scores combining TOMM40, mitochondrial haplotypes, KLOTHO, and others better capture resilience to age-related disease than single-gene models.

Hormonal Balance
The IGF-1 story is age-dependent: elevated levels in youth protect against metabolic and cardiovascular disease but in those over 60 are linked to higher rates of multiple morbidities and mortality. Women in the lowest half of IGF-1 lived twice as long and enjoyed superior cognitive function. Growth hormone, though beneficial for tissue repair (e.g., eight weeks post-biceps surgery), lacks clear longevity benefits and carries uncertain long-term risks. Intriguingly, modestly elevated TSH (5–8 mIU/L) in older adults correlates with longevity, prompting revisions in thyroid management guidelines to avoid overtreatment and potentially harness a slower-metabolism advantage.

Lifestyle & Environment
Centenarians often compress morbidity—30 percent reach 100 without chronic disease and suffer only months of decline. Exercise and nutrition remain cornerstones: high-intensity interval training and cold exposure boost mitochondrial biogenesis; strength outweighs hypertrophy for longevity; and dark leafy greens supply essential magnesium. Environmental stressors—intermittent fasting, temperature extremes, dietary plant compounds—activate hormetic pathways (e.g., Nrf2 via sulforaphane, AMPK via metformin) that promote cellular resilience.

Disease Prevention & Geroprotectors
Preventing chronic disease remains paramount. Metformin, originally an antimalarial and flu treatment derived from French lilac, is under trial (TAME) for reducing all-cause mortality; observational data suggest diabetic metformin users fare better than non-users, and small trials hint at cognitive benefits in mild impairment. Rapamycin and NAD⁺ precursors (NR/NMN) also generate intense interest. Yet metformin’s effects on exercise capacity and muscle hypertrophy warrant caution—and its use is best reserved for those with clear metabolic indications.

Socioeconomic & Psychological Dimensions
Extended healthspan carries economic upside—healthy elders spend, invest, and support families—while multi-generational bonds (great-grandchildren, shared experiences) enrich life’s meaning. Ultimately, genetics may set the stage, but environment, lifestyle, and the prevention of disease write the final act of a long, healthy life.