Jun 26, 2017, 4:59 PM ETPanel, Conference Presentation

Will You Live to a Healthy 100?

Shift from Lifespan to Healthspan: The panel prioritizes extending "health span" (years lived free of age-related illness) over simple chronological "lifespan."
Aging as a Risk Factor: Aging itself is identified as the primary risk factor for major diseases including cancer, heart disease, diabetes, and Alzheimer's.
Biological vs. Chronological Age: Researchers are developing markers to measure biological age, which may diverge significantly from a person's chronological age.
Clinical Transition: The conversation has moved from academic theory to actionable interventions, with experimental animals showing extended lifespans and human trials for specific interventions beginning.

Centenarian Resilience: Centenarians often experience a "contraction of morbidity," living full lives with high health span before dying rapidly, rather than suffering decades of chronic illness.
Genetic Variants: Specific gene variants (SNPs) and functional mutations in the growth hormone pathway have been linked to longevity; notably, reduced growth hormone activity may extend life.
Smoking Resilience: Some centenarians, such as a panelist's sister who smoked for 95 years, possess genetic resilience that negates the typical lifespan-shortening effects of smoking.
Health Span Extension: Longevity is strongly associated with an extended health span of 20–30 years, resulting in medical costs in the final two years of life that are roughly one-third of those for individuals dying at age 70.
Mitochondrial Function: Families of centenarians exhibit higher levels of mitochondrial hormones that support a more energetic and healthy aging process.

Telomere Function: Telomeres act as protective caps on chromosomes (like shoelace tips); they wear down over time, contributing to aging and age-related diseases.
Modifiable Lifestyle Factors: Lifestyle choices can influence the rate of telomere shortening, offering a handle for extending health span.
Senescent Cells: The panel discussed "zombie cells" (senescent cells) that stop dividing but persist, secreting inflammatory and potentially tumorigenic proteins that damage healthy neighbors; removing these cells in mice extended lifespan.
Protein Aging: Aging also involves the degradation of proteins in long-lived cells like neurons, requiring specific targeting strategies beyond telomere maintenance.

Definition of Aging: Aging is characterized as a loss of "homeostatic capacity"—the declining ability of the body to self-regulate and recover from stressors (e.g., blood pressure spikes, jet lag).
Investment Focus Areas: Investment is directed toward:
- Dynamic Biomarkers: Moving beyond static "state variables" (e.g., single blood pressure readings) to "resilience testing" (how the body responds to stress).
- Homeostatic Capacity Therapeutics: Drugs or interventions that improve the body's ability to return to equilibrium (e.g., exercise to raise blood pressure temporarily to improve long-term regulation).
- Genetic/Epigenetic Programming: Technologies targeting the plasticity of genetic programs to improve health span.
Market Opportunity: A projected "longevity dividend" of $7 trillion by 2050 exists if health span can be extended by two years.

Rapamycin: An mTOR inhibitor shown to extend lifespan in worms to dogs; currently in a placebo-controlled trial for dogs, but requires further development for safe human chronic use.
Metformin and the TAME Trial:
- Current Data: Metformin (a 60-year-old generic diabetes drug) shows observational evidence of delaying diabetes by 30%, cardiovascular disease by 30%, and reducing cancer and cognitive decline rates.
- The TAME Study: The "Targeting Aging with Metformin" trial plans to enroll 3,000 people aged 65–80 over 4–5 years to determine if Metformin delays the onset of multiple age-related conditions (cardiovascular, cancer, Alzheimer's) as a composite endpoint.
- Strategic Goal: The primary objective of TAME is to secure an FDA "indication" for aging as a disease, which would unlock pharmaceutical investment in geroprotective drugs.
- Projected Outcome: Conservative estimates suggest Metformin could extend health span by two years in humans.

Caloric Restriction (CR) Limitations:
- Genetic Variability: In mice, 30% of CR participants lived longer, 33% lived the same, and 10% lived shorter lives, indicating a need for personalized approaches.
- Primate Data: Large NIH-funded studies in non-human primates showed improved health markers (sleek coats) but no significant extension of lifespan via strict caloric restriction.
- Human Observations: Human mortality is often lowest in individuals with a BMI of 27–28 (slightly overweight), contradicting the strict low-BMI requirement of animal CR studies.
Alternative Dietary Strategies: Intermittent fasting and Mediterranean diets are suggested as more effective, proven human strategies for delaying mortality compared to strict caloric restriction.
Precision Longevity: Future interventions will likely be personalized based on genetic and epigenetic biomarkers (e.g., Metformin for diabetes risk, Rapamycin for cancer risk).

Trial Redesign: The TAME trial design has been updated to include comprehensive genomic, proteomic, and RNA markers, increasing costs by a factor of ten but aiming for precision medicine.
Timeline: The final review for the TAME trial is scheduled for June 16, with a potential start at the end of the summer pending co-funding from the American Federation for Aging Research and the NIH.
National Academy Challenge: The National Academy of Medicine has launched an "Aging and Longevity Grand Challenge" to incentivize innovations in extending health span.
Dynamic Range Optimization: Experts recommend increasing the body's dynamic range through varied stressors (exercise, diet variation) rather than relying solely on static drugs to maintain homeostatic capacity.
Investment Pledge: The panelists' foundations have pledged $2 million to support the National Academy's Grand Challenge and broader longevity research.