The Science of Looking Younger, Longer | Lifespan with Dr. David Sinclair #6
In a Nutshell
David Sinclair explains cosmetic aging interventions that slow or reverse skin thinning, hair loss, and graying while targeting biological aging via adversity mimetics like senolytics (e.g., navitoclax, rapamycin), peptides boosting collagen, retinoids, minoxidil, finasteride, LLLT, and PRP injections—contrasted with short-term abundance mimetics like Botox. Menopausal HRT (estrogen/progesterone matched to baseline levels) combats epidermal thinning and health risks; skin pinch test and epigenetic clocks gauge biological age, with UV avoidance, sunscreen, and lifestyle (no smoking/alcohol) essential. Upstream anti-aging (hormesis, autophagy) fixes external signs and extends lifespan, as validated by studies linking youthful appearance to lower mortality.
These notes were generated by AI and may contain inaccuracies.
Welcome to the Lifespan Podcast discussing the science of aging and how to be healthier at any stage of life. David Sinclair is a professor of Genetics at Harvard Medical School and co-director of the Paul F. Glen Center for Biology of Aging Research. This series covers why we age and interventions to slow, stop, and reverse aging. Last episode discussed cutting-edge science and procedures people are doing with doctors and might do in coming years.
Today focuses on slowing, stopping, and reversing aging of the outside of the body. Joined by co-author Matthew LaPlante. Initially skeptical about cosmetic aging episode but excited after preparation, especially parts about improving sexual function (separate episode planned). Discusses difference between interventions only for appearance and those impacting both appearance and aging. Covers keeping hair, skin, and nails looking young and reversing aspects. Nothing wrong with purely aesthetic interventions as they improve lives socially, emotionally, mentally even if not affecting biological aging. Centers on interventions with anti-aging effects.
Discusses coverups like Botox and creams, but most exciting are technologies boosting body's ability to fight aging and reverse it. Buckets: adversity mimetics (slow and reverse aging) vs abundance mimetics (short-term gain, look good, but long-term may not work or have deleterious effects).
Neglected discussion on hormones not found much in men: estrogen, progesterone. Pertains to menopause hormonal therapy and overall hormone replacement therapy (HRT) for women. Menopause affects first organ in woman's body to experience biological aging effects, sometimes in twenties but typically late thirties, early forties, before heart, lung, brain show damage.
Female reproductive system ages earlier; observed in mice studies on fertility (can reverse female infertility with stimulating molecules, discussed later). Humans evolved to have children up to age 30 then stop because childbirth was dangerous (1 in 5 chance of dying), required vigor, and raising kids takes at least a decade (now two decades). Continuous childbearing would divert energy from existing kids. Women evolved infertile around age 40; process is menopause, brutal for some: mood swings, vaginal dryness, loss of sex drive, migraines, hot flashes, increased susceptibility to heart disease.
Menopausal hormone therapy traditionally chiefly estrogen replacement, increasingly other hormones. Offers symptomatic relief. Past concerns of gnarly side effects and long-term damage, but learning more. Dual use of estrogen and progesterone in right combination, ratio, timing important. Early 2000s studies on cancer risk due to lack of understanding natural levels. Women should measure baseline estrogen and progesterone levels in thirties/forties during luteal phase of menstrual cycle so physicians can match in late forties/fifties. Monitoring essential for health state.
Recommendations for Hormone Monitoring
Use InsideTracker or doctor to measure levels, not just estrogen/progesterone but testosterone for men/women. Measure sex hormone binding globulin (SHBG); if too high, counteracts therapies. Dangers of menopausal HRT shouldn't scare off conversations with physicians. Right ratio/timing shows long-term protection against heart disease, bone loss, even extending therapy decades. Downsides if history of breast cancer (avoid estrogen).
Menopause effects include epidermal thinning, accelerated during/after menopause, also affects men with aging.
Athletic Greens: All-in-one daily green drink with 75 vitamins, minerals, whole foods, adaptogens, probiotics, prebiotics, digestive enzymes, vitamin C, zinc citrate. Covers nutritional bases, especially when traveling.
Levels: App syncs with continuous glucose monitor (provided), interprets glucose data. Monitors food impacts (e.g., white rice spikes blood sugar, potatoes don't). Stable glucose important for energy, long-term health.
InsideTracker: Personalized nutrition from blood/DNA analysis. Easy blood draw (clinic/home). Presents analysis, diet/lifestyle recommendations. InnerAge Test shows biological vs chronological age. 25% discount with code Sinclair.
Skin is largest organ, 1/6 of body weight, barrier to world. Skin health crucial for body health and vice versa; monitoring skin gives body health insights. Like checking fruit at grocery store for bruises, age.
Rest hand on table, pinch back of skin, release. Young skin (<30s/40s) pops down <2 seconds. 50s: many seconds. 60: 10-15 seconds. 70+: 30 seconds to minute. 80s/90s: 20-30 seconds. David's (50) pops right away due to interventions.
Epidermal thinning pernicious: skin protects from pathogens (e.g., COVID-19). Older skin bruises, rips, tears easily (paper thin). Critical in 70s-90s for life/death.
David Armstrong, top US surgeon for foot ulcers/wounds. 13% US population (40 million Americans) have foot ulcers now, mostly older people without societal voice. Ulcers hard to heal due to old skin; open, weeping, crusty quarter-size holes from minor trauma. With diabetes (loss of sensation), leads to infection, amputation. Nerves in skin; lose feeling with age. Story: patient stepped on thumbtack, didn't notice for days (heard tapping). Ulcers lead to cutting larger wounds, eventual amputation, death (worse than cancer diagnosis after 5 years).
Aging Affects Everyone
All aging; elder skin wrinkly, saggy, thinner means more than appearance.
Photos of ~300 elderly (Lothian Birth Cohort, Edinburgh, 1921 onwards) rated by another cohort for age, health, attractiveness, facial symmetry (from photos only). Followed 7 years: older-looking people (regardless of chronological age) more likely to die.
Nir Barzilai (Albert Einstein College of Medicine) studies centenarians. Photos show centenarian father looks 70, 70-year-old son looks 40. Fits "you are as old as you look."
Correlation with Epigenetic Clocks
2012 study appearance predictive of mortality but initial DNA methylation (Horvath clock) on blood didn't correlate. Different tissues have different clocks; skin-specific clocks work better. Mariana Boroni (Brazil, 2020 study): skin epigenetic clock from methylation predicts biological age well. Skin ages faster due to exposure (e.g., Australia UV damage accelerates epigenetic aging; identical twin in Norway younger skin). 1/3 Australians have skin tumor removed (not always lethal). Australian beaches now have free sunscreen pumps, saving billions in healthcare.
Prior generations without sunscreen have stuck damage, but can reverse.
Senolytics in Skin
Skin full of senescent cells (zombie-like, dysregulated epigenome, stop dividing, stain blue with beta-galactosidase). Common in older people; secrete inflammatory factors, mitogens (stimulate cancer). Deleting them in mice (increasingly humans) rejuvenates body.
Senolytic drugs treat internal organs and diabetes, but also rejuvenate skin. In a study, skin biopsies from people were grown ex vivo in tissue culture dishes and treated with senolytic drugs: ABT-263 (Navitoclax from Abbott) and rapamycin (mimics starvation or fasting). Skin explants grew thicker, reversing aging. They measured a special skin clock using DNA methylation patterns during skin aging, and senolytic treatment reversed the age of these skin pieces.
Senescent cells in skin, the body's largest organ, interact with all systems. They secrete cytokines that spread systemically. Lowering skin age can save the rest of the body. James Kirkland from Mayo Clinic found injecting a dab of senescent cells under mouse skin causes the whole mouse to age faster. Most senescent cells accumulate in skin due to UV damage.
Retroactively address with senolytics; proactively avoid UV with sunscreen. A little sunlight is beneficial for vitamin D, but excess causes sunburn (inflammation, swelling, tenderness). Go out 10-20 minutes daily without burning, wear sunscreen for longer exposure.
UV light hits DNA, fusing adjacent thymines (T-T dimer in ACTG bases). This creates a bulge enzymes can't read past for DNA opening, reading, copying. Cells cut out and replace them.
Old idea: T-T dimers cause mutations. New findings from Sinclair's lab and others: DNA repair process damages proteins, leading to cell identity loss.
Topical rapamycin or ABT-263 might work but rapamycin suppresses immunity; not available topically yet.
Dr. Boroni used skin explant beta-galactosidase stain (blue for senescence) to test 700+ peptides. Found ~20 with age-reversal effects; one in OneSkin product (Sinclair tried it, worked like retinol for fine lines/wrinkles). More peptides in development, showing efficacy in human trials.
Peptide boosts COL1A1 gene for collagen (key for flexible, thick young skin).
Collagen most abundant protein when young, holds bones/skin; declines after mid-twenties (babies plump). In beauty products, powders, drinks, pills, energy drinks. Degrades in stomach to amino acids; debate if intact peptides reach bloodstream. Jury out, but safe; ensures no amino acid deficiencies for collagen production.
Retinol and vitamin C better for protection, boost collagen, thicken epidermis/stratum corneum, reduce pigmentation ~60%, stimulate fibroblasts, lower lipids (anti-acne), promote keratinocyte growth for keratin (in skin, hair, nails).
Retinoids bind intracellular receptor, turn on genes for growth/benefits; inhibit MMPs (metalloproteinases breaking down skin). Can dry skin, increase sun sensitivity (use sunscreen, moisturize); avoid eyes.
Nail growth rate indicates biological age (1979 study glued measuring tapes on nails; Mr. Bean measured lifelong). Decreases ~0.5% per year. Monitor growth rate.
Retinoids induce autophagy. Ana Maria Cuervo (Albert Einstein) leads in autophagy research. Retinoic acid controls chaperone-mediated autophagy (CMA) via LAMP2A after 3-day fast (vs. shallow from skipping meals). Upregulating CMA extends mouse life 30-40%.
Retinoids stimulate growth (abundance mimetic), may shut down CMA (lifespan extender in animals). Balance hormesis: use retinols for wrinkles but not daily; rest, avoid during fasting for cleansing.
Oral/topical antioxidants largely ineffective for longevity (30 years trials: ingesting, injecting, genetic mods, skin application). Resveratrol works but not primarily as antioxidant; activates sirtuins, boosts defenses, metabolism, blood flow, oxygenation. Good in cosmetics for those reasons.
Nicotinamide, nicotinic acid (B3-related) in cosmetics thicken skin via sirtuin activation.
Sinclair developing NAD-boosting skin product.
HA for skin plumpness/flexibility (with collagen); throughout body, abundant in long-lived organisms, protects from cancer (e.g., naked mole rat cells produce HA jelly; removing it increases tumorigenicity). Vera Gorbunova's lab (Sinclair's child Alex assists) engineering HA-overproducing mice for cancer resistance.
Topical HA moisturizes well; for volume/laxity, consider injectable (large chains don't penetrate; use oligomers for skin synthesis). Resveratrol boosts HAS2 gene for HA enzyme (Sinclair lab patented).
Botox from Clostridium botulinum toxin (nanograms kill; 1g kills million people, 2kg humanity). Inhibits neurotransmission, relaxes muscles (e.g., forehead), reduces wrinkles 6-9 months (repeat injections). Purely cosmetic, not anti-aging/senolytic; improves appearance/social life (good for longevity).
Peels smooth skin, no age change. Microneedling (thousands of skin holes) induces hormesis, releases repair factors (potential long-term benefits, unproven).
Avoid sun, smoking (fastest skin aging accelerator, visible difference), alcohol (recent study), processed foods high in fats/chemicals. Diet affects skin/hair radically (seen in dogs, mice).
600+ genes for hair loss; ~20 on X chromosome (from mother, 11% male pattern baldness; females 50/50). Strong genetic component; slowed by anti-aging but genetically determined. Not life-threatening.
Early baldness not aging indicator; evolved in primates to signal age/dominance (graying, hair loss = wiser, like silverback gorilla).
In previous times,
In previous times, even just a few hundred years ago, being gray and distinguished was a real bonus.
Hair loss occurs due to stem cells in the bulge of the hair follicle that divide asymmetrically to produce other cell types. Types include those producing keratin for hair and melanocytes for color. A new type, hair follicle-associated pluripotent (HAP) stem cells, can be isolated and turned into bone and muscle; their exact role is unknown. During aging, key stem cells for hair regrowth get expelled from the follicle, a discovery from less than a few months ago. They do not die but are spat out. Preventing expulsion and maintaining their epigenome—their ability to remember their cell type—is crucial. Externally, since the 1960s, hair follicles shrink due to dihydrotestosterone (DHT), causing thinner hair until it stops the anagen phase (growth phase), versus catagen, telogen, and exogen phases.
Minoxidil (Rogaine) works; discovered in the 1960s while trying to lower blood pressure by stimulating nitric oxide production, which opens blood vessels (as in Viagra). Patients grew extra hair; in the 1980s, formulated with DMSO to penetrate skin, slowing hair loss mostly at the back and top of the head. Retin-A (tretinoin, retinol) at 0.5% promotes anagen; rub on thinning areas, especially with minoxidil. A study showed tretinoin with minoxidil resulted in regrowth in 66% after one year. Drawbacks: apply several times a day; oily, feels bad, many stop.
Finasteride (Propecia) is a once-daily pill inhibiting DHT via 5-alpha reductase enzyme. DHT reduces fat, benefits heart and mind, but enlarges prostate. Optimal levels for longevity: 9.8-15.8 nanomoles per liter, per study of 3,690 men—those levels lived longest. Eunuchs with minimal testosterone live 14-19 years longer; of 81 eunuchs, 3 became centenarians (1 in 27), vs. 1 in 4,400 in US population (130 times higher rate). Testes affect more than testosterone (e.g., brain, depression). Not recommended. Excess testosterone and growth hormone promote aging. Side effects: lowered sex drive, mood swings, depression, breast tenderness—low incidence; try and monitor with doctor.
LLLT uses red laser combs or caps for 10-15 minutes daily/every other day; FDA-approved, slows loss and regrows hair in majority via clinical trials. Mechanism unclear; likely mitohormesis—laser dissociates nitric oxide synthase from electron transport chain (complex V), producing free radicals that strengthen mitochondria, increasing energy for stem cells. Not heat. Red light penetrates skin, beneficial body-wide; rising sales of infrared saunas.
PRP: blood drawn, spun to isolate platelet-rich plasma, injected into scalp (anesthetized). Contains exosomes, hormones, peptides, VSELLs (very small embryonic-like stem cells), rejuvenating follicle stem cells. Used for injuries, longevity (veins). Exact active components unknown. Parallels heterochronic parabiosis: young blood rejuvenates old; components like GDF15. Future: purified versions as creams/injectables.
Hair grows excessively in nose, eyebrows, ears. Likely evolutionary remnant from hairier ancestors 6-10 million years ago; epigenome changes unravel silenced regions, activating ancient code. Slowing aging delays this.
Graying accelerated by stress; recent 2021 research on binary-colored hairs (dark-gray-dark) tied to stressful periods (no work stop, sleep, vacation). Proves reversibility—epigenetic, not genetic. Early gray splatters recoverable by resetting epigenome. Melanocytes next to hair shafts inject pigment into keratin; become dysfunctional before apoptosis death. Early intervention possible via adversity mimetics.
2023 study: cyclosporine A, minoxidil, tacrolimus (rapamycin/sirolimus analog, mTOR inhibitor, immunosuppressant) combo repigments. Cyclosporine preserves MPTP for mitochondrial rejuvenation, minoxidil improves blood flow, tacrolimus simulates fasting. Not ready for humans; some try rapamycin (10 mg weekly) under supervision. Future products likely.
Addressing aging upstream fixes hair, skin issues. Lessons apply body-wide: all cells share aging causes/defenses. Low-dose rapamycin, cyclosporine, minoxidil testable for other organs. Future: pills to reverse aging, regrow/repigment hair.
On verge of reversing internal/external aging for longer, better-feeling lives. Methods: injectables, edibles, smearables. Next 5-10 years promising. Looking good via right things (exercise, diet, sleep, low stress, adversity circuits) likely extends life. > "If you can keep yourself looking good by doing the right things, you'll probably end up living longer too."
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