The Science of Keeping the Brain Healthy | Lifespan with Dr. David Sinclair #7
In a Nutshell
The brain ages slower than the body due to protections like the blood-brain barrier, but longer lifespans increase dementia risk (e.g., Alzheimer's cases projected to double to 13.8M by 2060), driven by epigenetic changes where cells lose identity and accumulate damage like plaques. Combat this by activating longevity pathways (mTOR, AMPK, sirtuins) via Mediterranean diet (resveratrol, oleic acid, omega-3s), exercise (boosts BDNF, blood flow), metformin, and NAD boosters (NMN/NR 1g daily) to reverse cognitive decline, restore memories, improve sleep, and maintain mental sharpness. Modern evolutionary mismatch demands constant adaptation, so start early to sync brain and body aging for healthier longevity.
These notes were generated by AI and may contain inaccuracies.
Welcome to the Lifespan Podcast, where we discuss the science of aging and how to be healthier at any stage of life. David Sinclair is a professor at Harvard Medical School in the Department of Genetics, and co-director of the Paul F. Glenn Center for Biology of Aging Research. This podcast is about why we age, efforts, and things you can do in your daily life to slow, stop, and even reverse the aging process. In the last episode, talked about the skin, the largest organ in the body, and how to stay looking young and feeling good about yourself. Today, talking about the most important organ in the body, the brain. Joined by co-host Matthew, with whom wrote the book "Lifespan."
So far in this series, spoken about how aging impacts our bodies. No separation between our bodies and our minds, these are integrated systems, but up until this point, not talked much about the brain. Nobody wants to stay healthy in their body if they're not also healthy in their mind. Modern medicine has been very good at keeping most parts of the body healthy, like the heart with cardiovascular disease, cholesterol drugs, heart drugs. We're living longer, but not living better, because the brain is still aging and getting diseases. Alzheimer's and other types of dementia are becoming more prevalent because we're living longer, but not holistically slowing down the aging process.
Currently, about 6.2 million Americans over the age of 65 are living with Alzheimer's. That's just one of several forms of dementia. Because we're living longer, that number could grow more than twofold to 13.8 million by 2060 if we don't come up with some medical interventions that can prevent or reverse Alzheimer's disease. There's a recent drug that was approved, but it barely works, makes a minor difference. Need to make a breakthrough. What we're going to talk about today is a totally new approach to treating dementia, boosting the body's defenses against not just Alzheimer's, but against aging itself. Evidence that if you reverse the age of the human brain, Alzheimer's and other diseases of the brain will go away, and you'll even get your lost memories back again.
Not just about Alzheimer's today. Talking about other things that happen in the brain, molecular changes that make cells forget what type of cell they are, so nerve cells become more like skin cells. Another process important during aging, particularly about its reversibility, loss of blood flow.
All of us go through some amount of cognitive decline in our middle years. This isn't just about preventing things way downstream, this is about making our mental, intellectual lives better right now. The biological clock is ticking all the time, the epigenetic or Horvath clock, ticking from conception. What you do in your 20s and 30s will impact how healthy you are in your 70s, 80s, and 90s. It's never too early to listen to this podcast and do the kind of things we're talking about to slow down that clock.
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Aging is largely a result of epigenetic differentiation of cells. New science, not in textbooks. The new idea of aging is that it's not just random stuff going wrong, there's actually a program that begins at birth. During birth and prior, cells gain an identity. Start as a stem cell that's fertilized, cells differentiate identities: brain cells, skin cells, liver cells, tens of thousands of different types given specificity by turning on different genes out of the same genome through epigenetic signalers. The epigenome is the regulator of the genome, like the reader of a compact disc with 20,000 genes. Aging is due to scratches on the CD, so a brain cell starts to play the music of a liver cell or skin cell and doesn't function as well. Get diseases of aging, including Alzheimer's as a result.
Skin ages faster than most other systems. Used epigenetic clocks to measure aging in the brain, find the brain ages slower than the rest of the body, significantly slower. Very good chance your brain is biologically younger than you are. Studies led by Steve Horvath. Measured methylation on the DNA, a chemical called a methyl that cells add to the DNA, sticks there, ensures cells have identity and play right genes. With aging, that changes, can measure it. In lab, can do it for about a dollar. Readout tells biological age, e.g., 40-year-old brain actually 50, liver 55, skin 62.
Horvath looked at tissue samples from 112-year-old woman, regions of the brain much less methylated than other organs. Other studies showed across samples, predicted age lower in the brain than anywhere else, sometimes a quarter of the age of other parts.
Practical and evolutionary explanations. Brain protected by blood-brain barrier, doesn't get hit by UV light like skin, big thick skulls, protected from toxins. DNA breaks accelerate clock, happens naturally even to non-dividing cells like neurons. Cellular turnover relatively low in brain, could explain why doesn't epigenetic differentiate as fast. Unlike liver that regenerates, brain doesn't easily, little neurogenesis, nerve cells there for your whole life. Super protective mechanisms, adversity systems keep brain younger for longer, but not perfect. Ways to turn on those defenses greater than naturally activated.
Good news: brains age more slowly than rest of bodies. Bad news: living longer, bodies outliving brains in some cases. Average onset of dementia 80 years old, average lifespan in advanced nations more than 80. More living with dementia and cognitive impairments at ends of lives.
Work on aging, not Alzheimer's or cancer specifically. By working on aging, keep whole body young including brain for maximal gains in longevity, healthspan, mental capacity right up to the end. Whole body across lifespan. Everybody suffers some cognitive decline. Brain volume after age 40 reduces about 5% per decade, cognitive implications entering middle years.
Evolutionary sense that brain struggles at 30, 40, 50, but historically people didn't last that long, most males died in 40s-50s from predation, war, starvation. Some made it to 80s, but didn't need brains as 80-year-olds. Didn't need sophisticated executive functioning to survive in 30s-50s, life stayed the same. Getting gray, losing hair signs of wisdom. Now every year must learn something new, jobs turning over, started in 1700s, difficult even for young people to keep up. Plastic environment, ever-changing, implications for brain development and plasticity.
Watched grandmother shut down as she got older, didn't care about change, ignored computers, compact discs, last 20 years not great. Cannot ignore technology now or be isolated, e.g., during COVID-19 pandemic. Example at Apple store: 85-year-old woman getting new iPhone and iPad update. Our generation cannot slow down, must use Spotify, social media, adapt to job market changes, multiple jobs, remote work.
Keep brains and bodies aging at same rate to avoid physical and cognitive decline throughout lifespan. Comes down to three longevity pathways that respond to adversity, called adversity mimetics:
- mTOR: Responds to low amounts of amino acids, particularly leucine, isoleucine, valine.
- AMPK: Senses low energy, low glucose, makes more energy, more mitochondria, boosts NAD.
- Sirtuins: Require NAD, activated by certain chemicals.
They work together: sirtuins activate AMPK, AMPK activates sirtuins and mTOR. Downstream: turn up metabolism, burn fat, repair DNA, clear senescent cells, lower inflammation.
mTOR key role in autophagy, most potent. Responds to insulin signaling and fasting, mobilizes proteins to be recycled when hungry. Important for brain: misfolded proteins like lipofuscin in eye, plaques and tangles in Alzheimer's. Need deep cleansing, chaperone-mediated autophagy. Downregulating mTOR turns on recycling pathways effectively.
Lifestyle advice works for all three pathways since they communicate. Focus on sirtuins because central to brain health, respond to variety of environmental pseudo-stresses like food, exercise, supplements.
Several sirtuins, SIRT1 and SIRT6 important in brain, levels go down with aging along with fuel NAD. SIRT1 most important for controlling brain aging. Epigenetic clock ticks because loops and bundles of DNA get messed up. Sirtuins linked to that. When cell overstressed, sirtuins create DNA bundles for identity, but when chromosomes break, sirtuins rush to repair, then return to reestablish epigenome. 99.9% structures go back, but 0.1% accumulates as scratches causing aging.
To mitigate, upregulate sirtuins through NAD boosters. In 2008, upregulating SIRT1 in mouse nerve cells slowed aging, prevented loops and bundles changing, first evidence to slow mouse brain age. Can't modify human brains genetically yet, so use chemicals like resveratrol and NAD boosters, plus good diet and exercise, even better in combination.
Diet and exercise foundation. Mediterranean diet, one reason
Over a dozen studies show a Mediterranean-type diet protects the brain from aging and can reverse aspects of aging in the elderly with mild cognitive impairments. A study earlier this year led by Tommaso Boldrini from a large international research group showed higher adherence to the Mediterranean diet is associated with less amyloid beta, less tau, and larger gray matter volume—all linked to Alzheimer's disease. A second study by Anastasio et al. (2017) with nearly 2000 people found a 10% reduction in dementia risk for each point increase in Mediterranean diet score—the more Mediterranean the diet, the better. This includes olive oil, red wine, and limited red meat. The research team was from Greece.
Red wine contains polyphenols like resveratrol, which directly activates SIRT1, making the enzyme work faster like Pac-Man controlling genes. Resveratrol prevents cancer, has metabolic and brain-enhancing effects. Olive oil's oleic acid (also in avocados) activates SIRT1 by binding to it. Xenohormetic molecules from plants mimic stress, signaling potential food scarcity and activating longevity pathways. Plant-based diets like Mediterranean or Okinawan (low protein, mostly plants) trick the body into perceiving adversity, unlike calorie-rich Western or high-fat carnivorous diets that signal abundance and accelerate aging.
Plant-based diets risk deficiencies in folic acid (vitamin B9), B12, B6, and B3 (builds NAD for sirtuins). B vitamins ensure proper DNA methylation for the epigenetic clock. Low B12 impairs methylation, messes up the epigenome, accelerates aging, and links to heart disease and dementia. Low B vitamins elevate homocysteine levels—a marker doctors measure (ideal <10 micromoles/liter; >100 predicts imminent cardiovascular death). Keep homocysteine low with optimal B12 (measure it, e.g., via InsideTracker), avoid excess alcohol/smoking, note menopause/cancer/aging effects. Homocysteine indicates messed-up methylation; sirtuins can't compensate, leading to inflammation, plaque, arterial calcium buildup—manifesting as diseases but rooted in aging. High homocysteine correlates with dementia via brain vasculature clogging, stiff endothelial cells, occlusions reducing oxygen, causing memory loss and vascular dementia.
Ophthalmologists/opticians check retinal blood vessels (extensions of brain nerves) for occlusions/plaque via photos. Occlusions predict heart attack/death: 15% chance within a year, 50-50 chance of survival after 7 years (Hollenhorst, 1959). Eyes are a window into the brain.
Omega-3 fatty acids (EPA, DHA, ALA) are essential brain building blocks, often deficient even on normal diets. Fish (salmon, mackerel, krill, sardines) provide EPA/DHA (aim for ≥1g EPA daily; 1.6g EPA+DHA for men, 1.3g for women—improves memory, counters depression). Plant sources: ALA from flaxseed, walnuts, chia seeds, linseed oil (10% converts to EPA/DHA). Seaweed provides some DHA/EPA. Oleic acid (olive oil, avocados) is key. Consult doctor for ≥1g omega-3s daily. Omega-3s form myelin sheath insulation around nerves, protecting from inflammation/damage, aiding function/repair.
Dozens of studies show aerobic exercise/walking improves memory/cognition in aging via better blood flow, neuronal activity, sirtuin activation. Blumenthal et al. (2019): 160 sedentary adults >55 did 6 months aerobic exercise, greatly improving executive function (focus, concentration, task completion). Strength training also works: Perera et al. (2013) with 451 elderly found 10 weeks increased BDNF (brain-derived neurotrophic factor), promoting new brain cells/nerves. Exercise is crucial as activity declines with age—start early.
Metformin activates AMPK, crosstalks with NAD/sirtuin pathways, raises NAD via mitohormesis, stimulates NMN-to-NAD enzyme. Fish study (Nothobranchius guentheri): Metformin in food improved memory tasks (light-food association, mazes, fear conditioning) in aging fish. Mechanistically, metformin enters mitochondria, disrupts electron transport chain, releases free radicals (mitohormesis), boosts mitochondria production, sends GLUT4 to cell membrane lowering blood sugar (prevents protein glycation/dysfunction). Mouse/rat/human studies confirm: Koenig et al. (2017) randomized placebo-controlled crossover (20 non-diabetics with mild dementia) improved executive function—suggests reversibility. Large 2019 study: 55% lower dementia incidence in metformin-using diabetics vs. non-users. Metformin may directly bind/activate NAD enzyme like resveratrol (one study; replication pending).
Animal research shows NAD elevation improves cognitive function, aids brain injury recovery. Brain NAD declines with less NAMPT enzyme (activated by metformin/exercise).
Jeffrey Milbrandt at Washington University showed in high-profile papers in recent years that an enzyme called SARM1 gets turned on in nerve cells when damaged, rapidly depleting the cell of NAD. There's a decrease in NAD production and an increase in NAD degradation. Supplementation is important to restore youthful NAD levels and go beyond, mimicking exercise and a perfect diet, especially for the elderly who cannot always do those things.
Research on NAD supplementation for brain health dates back almost 20 years. A 2004 study showed NADH treatment slowed Alzheimer's.
NADH is NAD with a hydrogen atom attached; NAD+ has a positive charge like the end of a battery. NADH attaches hydrogen to the vitamin B3 part of NAD. NAD has two major functions: turning on sirtuins, DNA repair, and acting as a hydrogen carrier moving hydrogens between places.
NADH gets into the bloodstream, gets degraded into components—vitamin B3, phosphate, nucleotide (A letter)—and reassembled into NAD+. You're giving components in concentrated form.
A recent result: combination of NR (NAD booster) and pterostilbene slowed ALS progression.
NR is nicotinamide riboside: cell takes vitamin B3 (niacin or nicotinamide), turns it into NR (adds ribose), then NMN (adds phosphate), then NAD.
Taking ~1 gram NR in humans makes NMN and higher NAD levels. ALS patients benefited greatly.
Pterostilbene is resveratrol with three methyl groups, delivering resveratrol plus NAD booster in pill form.
Short-term study showed immediate returns for ALS patients. Lenny Guarente at MIT (Sinclair's former mentor) is running a year-long study to see if results continue for this debilitating disease with no cure or effective treatment. Most trials fail phase one; this is phase two.
NMN and SIRT1 activity maintain youthfulness and ability to grow new blood vessels in mouse muscle and brain. Collaboration with Zoltan Ungvari at University of Oklahoma: elderly mice on NMN had better blood flow, thought and remembered better due to vascular improvements.
Blocking SIRT1 in endothelial cells lining blood vessels eliminated NMN benefits. This turns mice with older brains into mice with younger brains, reversing an aspect of aging by restoring learning ability.
Overexpression of SIRT1 in all nerve cells extends mouse lifespan and protects against induced ALS, Huntington's, and Alzheimer's.
Hippocampus (secretes hormones reducing blood glucose by talking to liver; consolidates memory): activating with resveratrol or more SIRT1 copies improved memory in old mice.
SIRT1 plays an amazingly important role in delaying aging, preventing diseases of aging in mice, and potentially humans.
Hypothalamus controls circadian rhythm. SIRT1 and NAD rise in morning, fall later, preparing body for sleep. They turn on BMAL gene (circadian clock gene), calming liver and brain at night, waking everything in morning.
Low SIRT1 or NAD impairs sleep and causes premature aging. Sleep efficiency declines with age, requiring harder work like exercise for brain health.
As you get older, you lose ability to sleep. If you don't sleep well, you lose ability to fight aging. Feed-forward disaster.
Intervene with eating well, exercise, supplements.
Sinclair takes 1 gram NMN in morning to raise NAD, uses it when traveling to reset body and avoid jet lag.
Other supplements: magnesium, L-theanine for calming at night. Avoid late emails, relax brain.
Best for sleep: get light right upon waking to reset rhythms, signal daytime.
Get outside or use blue light (e.g., in Boston winter) to raise cortisol synthetically, boost energy, sync rhythms.
2020 fruit fly study: sleep deprivation causes oxidative stress in gut, short lifespan; rescued by NAD booster.
One night sleep deprivation increases amyloid beta production by 5%, which accumulates in brain.
Sleep-restricted rats get diabetes in two weeks.
2010 Capucho et al. study (1 million people): very little sleep raises mortality risk 30% vs. normal sleep.
Brains face constant modern adversity; sleep resets.
Work to keep brains healthy longer than the body. Evolved brains to last shorter than now-extended lifespans.
Responsibility to family and society: avoid burden of dementia care.
Upcoming: wearables, monitors, age reversal tech reversing Horvath DNA methylation clock by decades. Home testing, reprogramming (e.g., eye discovery taking world by storm, billions invested). Things from book accelerating faster than expected.
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