Rethinking Medicine to Live Longer

By Peter Attia, MD with Bill Gifford

Part I

• Mainstream medicine insists on waiting until the point of diagnosis before we intervene - Type 2 diabetes example (page 13)
• Medicine 3.0
  • places a far greater emphasis on prevention than treatment
  • considers the patient as a unique individual
  • starting point is the honest assessment, and acceptance, of risk - including the risk of doing nothing
  • medicine 2.0 focuses largely on lifespan, and is almost entirely geared toward staving off death, medicine 3.0 pays far more attention to maintaining healthspan, the quality of life
• Currently - nearly all the money flows to treatment rather than prevention
• Three part approach to longevity: objective - strategy - tactics
• Used to prioritize nutrition over everything else but now considers exercise to be the most potent longevity “drug” in our arsenal, in terms of lifespan and healthspan. The data are unambiguous: exercise not only delays actual death but also prevents both cognitive and physical decline, better than any other intervention. We also tend to feel better when we exercise, so it probably has some harder-to-measure effect on emotional health as well.

Part II

Centenarians: The Older You Get, the Healthier You Have Been

• Genes in centenarians that could be helpful: e2 variant of APOE, CETP, APOC3, FOXO3
• Another flaw of medicine 2.0 - it generally looks at diseases as entirely separate from one another

Eat Less, Live Longer: The Science of Hunger and Health

• mTOR
  • turns out to be one of the most important mediators of longevity at the cellular level
  • highly “conserved,” meaning it is found in virtually all forms of life
  • The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, as with the ultimate goal of reproduction. When nutrients are scarce, mTOR is suppressed and cells go into kind of “recycling” mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.
  • to some extent, like the general contractor of the cell and basically has a finger in every major process in the cell
• Many of the most headline-grabbing studies, the ones you read about in the newspaper or see reported on the news, are never repeated (example: reservatrol)
• The life-extending effect of calorie restriction seems to almost universal. Numerous labs have found that restricting caloric intake lengthens lifespan not only in rats and mice (usually) but also in yeast, worms, flies, fish, hamsters, dogs, and even, weirdly, spiders. It has been found to extend lifespan in just about every model organism on which it has been tried, with the off exception of houseflies.
  • CR’s usefulness remains doubtful outside of the lab; very lean animals may be more susceptible to death from infection or cold temperatures.
  • The real value of caloric restriction research lies in the insights it has contributed to our understanding of the aging process itself
• Reducing the amount of nutrients available to a cell seems to trigger a group of innate pathways that enhance the cell’s stress resistance and metabolic efficiency - all of them related in some way, to mTOR
  • First of these is an enzyme called AMP-activated protein kinase. AMPK prompts the cell to conserve and seek alternative sources of energy. It does this first by stimulating the production of new mitochondria, the tiny organelles that produce energy in the cell, via a process called mitochondrial biogenesis.
  • Over time - or with disuse - our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunction and failure. Restricting the amount of nutrients that are available, via dietary restriction or exercise, triggers the production of newer, more efficient mitochondria to replace old and damaged ones. These fresh mitochondria help the cell produce more ATP, the cellular energy currency, with the fuel it does have. AMPK also prompts the body to provide more fuel for these new mitochondria, by producing glucose in the liver and releasing energy stored in fat cells.
  • AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it all the anabolic (growth) processes that mTOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating an important cellular recycling process called autophagy, which means “self-eating (or better yet, “self-devouring”).
  • Autophagy - form of cellular recycling, cleaning out the accumulated junk in the cell and repurposing it or disposing of it.
  • Impaired autophagy has been linked to Alzheimer’s disease-related pathology and also to amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and other neurodegenerative disorders.
  • By cleansing our cells of damaged proteins and other cellular junk, autophagy allows cells to run more cleanly and efficiently and helps make them more resistant to stress. But as we get older, autophagy declines. Impaired autophagy is thought to be an important driver of numerous aging-related phenotypes and ailments, such as neurodegenerative and osteoarthritis…This important cellular mechanism can be triggered by certain kinds of interventions, such as temporary reduction in nutrients (as when we are exercising or fasting) - and the drug rapamycin.
  • Rapamycin also seems to reduce systemic inflammation. Apparent immunosuppressive effects. Giving the drug daily, as is typically done with transplant patients, appears to inhibit both complexes, while dosing the drug briefly or cyclically inhibits mainly mTORC1, unlocking its longevity-related benefits.

The Crisis of Abundance: Can Our Ancient Genes Cope with Our Modern Diet?

• NASH - nonalcoholic steatohapatitis