Super Agers: An Evidence-Based Approach to Longevity

Topol explains why advances in treating rare diseases are central to improving health span for everyone. Though individually uncommon, rare diseases collectively affect over 400 million people worldwide, with most having genetic origins. Genome editing, particularly CRISPR technology, is transforming treatment approaches by targeting disease-causing mutations directly.

Topol uses familial hypercholesterolemia as an example. Traditional treatments like statins can help, but CRISPR-based editing of the PCSK9 gene offers the potential for a one-time therapy to permanently reduce LDL cholesterol. This illustrates how treatments developed for ultra-rare disorders may scale to common diseases like heart disease.

The chapter traces CRISPR’s development into a precise editing tool. CRISPR 1.0 relied on double-strand DNA breaks, often causing random errors, while CRISPR 2.0 methods like base and prime editing allow targeted, efficient, and potentially safer modifications. These newer approaches could fix up to 90% of known disease-causing mutations.

Clinical milestones include the approval of the drug Casgevy in 2023 for sickle cell anemia and beta-thalassemia, though treatment remains complex and burdensome, often requiring ex vivo editing (cells removed from and modified outside of the body, and then reintroduced to the patient) and chemotherapy. Moving toward in vivo, one-shot editing within the body is a key goal, with early successes in primates and human trials.