How could we reverse aging? | Ronald DePinho | TEDxFordhamUniversity

Key Concepts:

• Aging as a disease
• Hallmarks of aging (DNA damage, inflammaging, mitochondrial dysfunction, senescent cells, telomere attrition)
• Telomeres and telomerase reverse transcriptase (TERT)
• TERT's dual function: chromosomal integrity and gene expression regulation
• Therapeutic intervention to restore TERT levels
• TAC (TERT activator compound)
• Healthspan vs. lifespan
• Regenerative medicine vs. reactive sick care

1. Introduction: Aging as a Targetable Disease

• Aging is presented not as an inevitable process but as a disease that underlies major age-related conditions like cancer, diabetes, heart disease, and Alzheimer's.
• The speaker emphasizes the significant economic and social impact of aging, citing the statistic that there are 1.2 billion people over 60, with a geometric increase in disease incidence every five years after that age.
• Specific examples: Lifetime risk of cancer is 40%, and nearly 40% experience some form of dementia by age 85.

2. Defining Aging: From Description to Molecular Mechanisms

• The traditional definition of aging is described as "gradual accumulation of damage and loss of function in cells and organs over time."
• The speaker argues that a mechanistic understanding of aging at the molecular and cellular level is crucial for therapeutic intervention.
• Analogy to cancer: Understanding mutations in cancer has led to targeted therapies.

3. Hallmarks of Aging: The Molecular Drivers

• The hallmarks of aging are presented as key targets for intervention:
  • DNA Damage: Accumulation of damage leading to genomic instability.
  • Inflammaging: Chronic, unrelenting inflammation that damages organs.
  • Mitochondrial Dysfunction: Decline in energy production and increased free radical production.
  • Senescent Cells (Zombie Cells): Accumulate in tissues, causing inflammation and organ atrophy.
  • Telomere Attrition: Shortening and damage of telomeres, leading to chromosomal instability and premature cell aging.

4. Telomeres and Telomerase: Maintaining Chromosomal Integrity and Youthful Gene Expression

• Telomeres are described as the tips of chromosomes that maintain chromosomal integrity.
• Telomerase reverse transcriptase (TERT) is an enzyme that maintains telomere length. Its discovery won a Nobel Prize.
• TERT has a "moonlighting function": it associates with transcription factors that regulate genes associated with a youthful cell state.
• The speaker's research showed that TERT levels decrease with the onset of aging, triggering a cascade of events leading to the hallmarks of aging.

5. Therapeutic Intervention: Restoring TERT Levels with TAC

• The research team screened about a million compounds to find drugs that could restore youthful TERT levels.
• They identified two structurally related compounds, one of which was dubbed TAC (TERT activator compound).
• TAC restores TERT levels, penetrates all cells (including crossing the blood-brain barrier), and has a short half-life, requiring administration only three times a week.

6. Experimental Results: Reversing Aging in Mice

• Mice aged 22 months (equivalent to humans in their 70s) were treated with TAC for six months.
• The results were striking:
  • Increased neurogenesis (new neuron formation) in the hippocampus (important for working memory).
  • Enhanced learning and memory.
  • Elimination of senescent cells.
  • Reduced inflammation.
  • Increased neuromuscular function (strength, balance, speed, coordination).
  • Improved immunity.
  • No side effects due to the short half-life and intermittent administration.

7. Application to Alzheimer's Disease: Reducing Amyloid Plaques and Neuroinflammation

• Mice genetically engineered to develop Alzheimer's-like pathology were treated with TAC.
• Results showed:
  • Greatly reduced amounts of amyloid plaques (protein gunk that destroys neurons).
  • Less neuroinflammation (reduced and less activated microglia).

8. Conclusion: A New Era of Regenerative Medicine

• Aging is not inevitable; it's a biological process that can be influenced by science.
• The speaker envisions a shift from reactive "sick care" medicine to proactive regenerative medicine.
• The goal is to increase healthspan (years of healthy living) rather than just lifespan.
• Compressed mortality: more years of healthy living, delaying the onset of age-related diseases.
• The speaker concludes with a vision of a future where people can remain healthy, active, and productive well into their 90s.
• A final perspective is mentioned, referencing Steven Coar, who often holds an opposite view.