Path 12: Holistic Damage Repair (SENS Approach)

Rationale: Combining forces: engineering negligible senescence. This broad engineering strategy repairs all forms of aging damage faster than they accumulate, exemplified by Aubrey de Grey’s SENS. It breaks aging into categories of damage (cell loss, death-resistant cells, gene mutations, protein aggregates, cell senescence, crosslinking, etc.) and proposes specific interventions for each. Even if aging has multiple causes, we may not need to understand every nuance if we can identify and fix the damage.

Prerequisites: A bit of everything – cell biology, biomedical engineering, gene therapy, gerontology.

Dependencies: Basically Paths 2–11 combined. Assumes all major forms of damage matter, so depends on progress in each specialized path.

Signs of Progress: A unified therapy cocktail addressing multiple hallmarks at once. Mouse lifespan extension beyond any single intervention (aiming for 2×). Iterative rejuvenation: middle-aged mice restored to youthful function by combination treatment applied repeatedly. Multi-modal clinical approaches in humans.

BC12.1: Categories of Damage (The SENS Paradigm)

Scope: Enumerate the seven categories: (1) cell loss/atrophy, (2) death-resistant cells (senescent), (3) DNA damage, (4) mitochondrial mutations, (5) extracellular junk, (6) intracellular junk, (7) extracellular crosslinks.

• de Grey, Aubrey & Rae, Michael. Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime. St. Martin’s Press, 2007. – Outlines SENS in layman’s terms.
• de Grey, A. “Strategies for engineered negligible senescence.” Ann. N.Y. Acad. Sci., 2004. – Earlier technical description, category by category.
• Hall, S.S. “Trends in aging: The anti-aging surgeon.” Science, 2003. – Journalistic perspective on SENS, including supporters and skeptics.

BC12.2: Multi-Intervention Studies

Scope: Combinations of therapies in animals. Interventions Testing Program (ITP) synergy examples.

• Strong, R. et al. “Combination of rapamycin, acarbose, and phenylbutyrate extends life span.” J. Gerontol. A, 2022. – Triple combo saw additional lifespan gains – proof-of-concept for synergy.
• Richardson, A. et al. “The NIA Interventions Testing Program.” Gerontology, 2016. – How ITP works and what’s been found effective.
• Barzilai, N. et al. “Geroscience: Linking Aging to Chronic Disease.” Cell, 2018. – Targeting aging to combat multiple diseases, likely requiring multiple interventions.

BC12.3: Bioengineering Approaches

Scope: LysoSENS enzymes, whole organ replacements, CRISPR gene editing, young organoid transplantation.

• Mendonça, M. et al. “Gene therapy strategies for lysosomal storage diseases based on the SENS platform.” Rejuvenation Res., 2015. – Delivering enzymes to degrade wastes.
• Daniel, M.G. & Tenen, D.G. “Improved human healthspan and lifespan by reversing immunosenescence in the thymus.” J. Exp. Med., 2019. – TRIIM trial commentary: if thymus, what about other organs?
• Wu, R.A. et al. “An expandable life-span chronometer mouse for aging studies.” Cell, 2022. – New transgenic mouse tech enabling faster combination therapy testing.

BC12.4: Ethical and Practical Considerations

Scope: Societal impacts of indefinite lifespan, cost/complexity, regulatory challenges, risk of overselling.

• Olshansky, S.J., Hayflick, L. & Carnes, B.A. “No truth to the fountain of youth.” Sci. Am., 2002. – Skeptical take cautioning against dramatic life extension claims.
• de Grey, A. “Cryonics, uploading and other transhumanist scenarios.” Chapter in The Transhumanist Reader, 2013. – How proponents address ethical issues.
• Justice, J. et al. “Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes.” J. Gerontol. A, 2016. – How to test multi-faceted interventions in humans.

Bibliography (Path 12)

• de Grey, Aubrey D.N.J. et al. “Time to Talk SENS.” Ann. N.Y. Acad. Sci. 1197(1): 133–139, 2010. (De Grey’s rejoinder to critics, clarifying SENS approach)
• de Grey, Aubrey D.N.J. Ending Aging. St. Martin’s Press, 2007. (Book explaining seven categories of damage and proposed therapies)
• Rae, Michael et al. “The Demographic and Biomedical Case for Late-Life Interventions.” Sci. Transl. Med. 2(40): 40cm21, 2010. (Even late-life interventions can have large benefits)
• Justice, J.N. et al. “Frameworks for Proof-of-Concept Clinical Trials.” J. Gerontol. A 71(11): 1415–1423, 2016. (How to test geroprotective therapies in humans)
• Hall, Stephen S. “Trends in Aging: The Anti-Aging Surgeons.” Science 312(5782): 1116–1118, 2006. (Fringe and mainstream efforts, ethical and regulatory issues)