Peter Attia MD171- Longevity science: caloric restriction studies, aging biomarkers & possible longevity molecules
CHAPTERS
- 0:02 – 7:19
Steve Austad's Unusual Childhood and Path Through College
Peter Attia opens by asking about Steve Austad's background. Austad describes being a math nerd who switched to English, a childhood spent traveling in a house trailer, and a delayed growth spurt.
- •Austad was a math nerd in high school and a rattlesnake-catching enthusiast who ended up an English major
- •His father, a newspaper pressman, moved the family constantly, so Austad attended roughly 20 grade schools
- •He studied from books in the back seat of the car and helped bigger kids with homework to avoid being beaten up
- •He was tiny in high school, got injections for delayed puberty, and grew mostly after starting college
- 7:19 – 12:12
Driving a Taxi in 1970s New York
Wanting experiences to fuel a novel, Austad moved to New York and drove a cab at night. He recounts the city's rougher state in the mid-1970s and a few dicey fares.
- •He hitchhiked to New York and drove a taxi to accumulate experiences
- •He hid his ignorance of confusing areas by asking passengers which route they preferred
- •A passenger who wanted to stop at every bar while looking for his wife ended the ride when Austad asked why
- •He took fares to Harlem and was never robbed, which he credits to luck
- 12:12 – 20:04
Accidentally Becoming a Lion Tamer
Back in Portland, Austad's karate teacher asked him to help drive lions to Hollywood. The trip led to a job training lions, including a stint living with Tippi Hedren's family, and ultimately to a serious lion attack.
- •The lion rode in the backseat with no barrier, and the cattle prod's battery died during the drive
- •A police stop ended with the lion stepping on the car horn and the officer telling them to leave his jurisdiction
- •The movie producer offered Austad a job on the spot, which he accepted after learning it involved living with Tippi Hedren
- •A lion attack in Acton, California left him hospitalized and prompted him to rethink his future
- 20:04 – 30:36
From Grad School and Opossums to an Interest in Aging
After the attack, Austad went to graduate school and did a PhD on animal combat models. Studying opossums in South America, he saw how quickly they aged, which began his interest in aging, and he went on to run island-versus-mainland opossum studies at Harvard.
- •His PhD used math to model animal combat and had nothing to do with lions
- •South American opossums developed cataracts, muscle loss and parasites by 18 months, sparking his interest in aging
- •At Harvard he compared North American opossums on a predator-free island with mainland ones and found about a 20% difference in aging
- •He never ran the genetic swap experiment, and his lab colony was lost to infection
- 30:36 – 43:50
What the Laboratory Mouse Really Is
Coming from field biology, Austad became interested in how laboratory evolution has changed lab animals. He describes the history of inbred lab mice, how bizarre they are compared with wild mice, and why heterogeneous mouse models and rats matter.
- •Lab mice descend from 'fancy mice' and were inbred brother-sister for hundreds of generations, making strains like B6 homozygous at every locus
- •Lab mice are at least twice as big as wild mice, mature twice as fast and have bizarre mutations
- •The ITP's genetically heterogeneous mice are a step forward but all share the same mitochondria
- •Wild-derived genes tend to be lost in captivity, and Austad says even the best mouse is still just one species
- 43:50 – 57:33
Clive McCay, Roy Walford and the History of Caloric Restriction
Austad traces caloric restriction research from Clive McCay's 1930s rat experiments through postwar researchers like Roy Walford and Ed Masoro. The discussion includes Walford's Biosphere 2 experience and a comparison of rats and mice.
- •McCay was studying growth, found that feeding animals less extended life, and never followed up on it
- •Austad's own spider data from his PhD showed that less food meant longer life
- •Walford believed the immune system underlies the effect, while Masoro used CR to test hypotheses about aging
- •Biosphere 2 became an inadvertent CR experiment, and Walford attributed his later health problems to the low-oxygen air rather than the diet
- •Rats have far greater genetic and mitochondrial diversity than lab mice, and Austad wants to bring them back into aging research
- 57:33 – 1:13:01
The Wisconsin and NIA Monkey Studies
Austad and Attia compare the two large rhesus monkey CR experiments, which reached different conclusions. They examine how the control groups and diets differed, with Wisconsin using a roughly 28% sucrose diet versus about 3% at the NIA.
- •Wisconsin fed controls ad libitum and restricted others by 30%, finding CR monkeys lived longer and were healthier
- •The NIA fed controls to a healthy weight and found no lifespan benefit from CR
- •Attia notes the Wisconsin diet was high in sucrose, equivalent to Big Macs, fries and Cokes, while the NIA diet resembled a Whole Foods pescatarian diet
- •Attia concludes the worse the diet, the more benefit from restriction, and Austad notes huge glucoregulatory problems in the Wisconsin controls
- •Housing differences, isolation and uncertain ages and origins further complicate the comparison
- 1:13:01 – 1:28:23
Caloric Restriction in Wild Mice and Why It Might Backfire
Austad describes his own experiment restricting the diet of wild-derived mice in the lab and how wild mice differ from lab mice. He then explains why he thinks CR would shorten life in the wild.
- •Restricting wild mice brought no average lifespan difference, though the longest-lived mice were all in the restricted group and some restricted mice died early
- •Wild mice bite, jump and fail standard lab tests, and wild-derived mice live about 20% longer in the lab than lab mice
- •Supplementing food in the wild lengthens life because animals forage less and face less predation
- •Austad says CR slows wound healing and raises susceptibility to some pathogens, which matter in the wild
- •Nature selects for reproduction rather than maximal lifespan
- 1:28:23 – 1:38:23
Human Calorie Restriction Studies and the CR Society
Austad reviews the human CR evidence, including Biosphere 2, the CALERIE trials and the extremely lean members of the Calorie Restriction Society. He notes that most people can't sustain real restriction, and the results are hard to interpret.
- •Participants in the CALERIE trials achieved only about 11-12% restriction over two years instead of the 25% goal
- •Cardiovascular risk factors improved but bone mineral density fell and some strength was lost
- •Austad says moving borderline overweight people to a healthy weight is unsurprising and any physician would expect benefit
- •CR Society members have BMIs of about 17-20, low sex hormones, low thyroid hormone and little muscle, and are an uncontrolled, self-selected group
- •Both agree constant 30% restriction is a non-starter for most people
- 1:38:23 – 1:45:57
Fasting, Time-Restricted Eating and Dietary Alternatives
Attia lays out alternatives to constant CR, such as time-restricted feeding, dietary changes and intermittent fasting. Austad discusses the timing hypothesis, mTOR, and Jay Mitchell's finding that short fasts protected mice from lethal ischemic injury.
- •Attia frames time-restricted feeding, dietary restriction and intermittent fasting as routes out of the standard American diet
- •Austad says these approaches are new and mostly tested in people with health issues, though the logic is compelling
- •Lab rodents fast about 23 hours a day, so timing may matter as much as total intake
- •Mitchell's mice fasted for two or three days survived kidney and liver ischemia-reperfusion injury that killed most ad lib-fed mice
- •Austad suggests 'food restriction' may be a better name than calorie restriction
- 1:45:57 – 1:50:53
Macronutrients, Biomarkers and Starting Late in Life
The discussion turns to which nutrients matter and why human studies need biomarkers to be practical. Austad highlights the ITP finding that interventions started late in life can still help, and describes first noticing his own aging.
- •Austad says animal work won't settle which macronutrient mix is best, so experiments in healthy people are needed
- •Long-term diet trials are risky, so short-term biomarkers that predict long-term outcomes are needed
- •The ITP shows interventions started late in life can still produce dramatic benefits
- •Austad recalls noticing he'd 'lost a step' in a pickup basketball game around age 30 to 32
- 1:50:53 – 2:10:18
Why Women Outlive Men and Why Alzheimer's Differs
Austad explains that women survive better at every age and under nearly all conditions, and the cause is unknown. They consider sex hormones, behavior, X inactivation, mitochondrial compatibility and Y-chromosome genes, and Austad offers a private hypothesis about Alzheimer's.
- •The female survival advantage is about five years and holds from infancy through old age and across epidemics and famines
- •Two weak, post hoc studies of castrated men showed longer life, while hormone replacement evidence is debated
- •Austad proposes the extra X's redundant genes, mitochondrial-nuclear compatibility, and Y-chromosome genes expressed in every tissue as possible explanations
- •Women die at lower rates from all major causes except Alzheimer's, and Austad guesses it may have an autoimmune component
- •In the ITP, rapamycin's sex bias depends on dose, and mouse sex chromosomes differ from human ones
- 2:10:18 – 2:17:19
The Search for Aging Biomarkers
Attia asks why better aging biomarkers haven't emerged. Austad says earlier efforts failed but he is optimistic, and they debate epigenetic clocks versus proteomic and metabolomic markers and the funding problem.
- •The NIA spent about $100 million on aging biomarkers in the 1990s and produced nothing, perhaps because the tools weren't ready
- •Attia is unimpressed by epigenetic clocks because they swing with short-term changes like a three-day fast, while Austad is more impressed but thinks they may only matter over years
- •Austad thinks the proteome and metabolome are likelier to yield therapeutically useful markers
- •Attia says diagnostics are commercially unattractive and would need a Manhattan Project-style effort
- 2:17:19 – 2:21:35
The 150-Year-Old Bet and the Limits of Human Lifespan
Austad explains his wager with Jay Olshansky about the first 150-year-old human and why he still expects to win. They also discuss what limits life expectancy and why cause-of-death elimination models mislead.
- •Austad bet that the first 150-year-old was already born by 2000, and the person had to be mentally competent
- •He expects it would take something that fundamentally slows aging, not better cancer or heart disease treatment
- •Austad is talking about one person, not life expectancy, and thinks average life expectancy might reach about 100
- •He says Olshansky's models assume causes of death are independent, and eliminating one cause isn't the same as delaying many
- 2:21:35 – 2:34:58
Promising Longevity Molecules: Rapamycin, Metformin and Beyond
Attia asks which existing molecule holds the most promise for geroprotection. Austad favors rapamycin on mouse data and metformin on human data, and they discuss how to dose rapamycin, SGLT2 inhibitors and why biomarkers remain the limiting factor.
- •Austad names rapamycin as the best bet from mouse data and metformin from human data, and suspects combinations may be best
- •Metformin's human evidence comes largely from diabetics and it failed in the ITP, so Austad would not be surprised if it fails in healthy people
- •For rapamycin he would start with the low, episodic everolimus doses used in the older-adult vaccine studies, which had fewer side effects
- •Austad says it's too early to judge SGLT2 inhibitors and NAD precursors and that he is never excited by a single mouse study
- •Austad regrets the ITP dropped its pair-fed arm and says the limiting factor is human biomarkers
