Modest Life Extension in Yeast by Reducing Intentional DNA Damage
Double-strand breaks in nuclear DNA are one of the more severe forms of DNA damage, though not as bad as large deletions as little to no information is lost, and in a healthy and young cell even a double-strand break is quickly repaired. Interestingly, double-strand breaks can occur intentionally in the cell, a part of its normal operation, and are thus not only the result of haphazard chemical reactions. This does make age-related failure of DNA repair mechanisms a more serious matter: unrepaired double-strand breaks are harmful to cells, and a higher rate of such breaks could promote, for example, more cellular senescence, known to contribute to the aging process. You might look way back in the archives at the late Robert Bradbury's double-strand break view of aging for related thoughts on this topic. Could we get by with fewer intentional double-strand breaks, and would that somewhat slow the course of aging? Here, an initial study on this question suggests the answer is yes, at least in yeast cells, though I suspect the situation to be more complex in higher forms of life.
Researchers have demonstrated a causal relationship between reduced DNA damage and extended lifespan, identifying a cellular factor - an enzyme called topoisomerase 2, or Top2, implicated in DNA damage - that can be targeted to reduce that damage. Top2 introduces double strand breaks into DNA as part of its catalytic cycle. The breaks must then be resealed. "Every once in a while Top2 gets trapped on the DNA before it can seal the breaks. When that happens, at least in young cells, there are a number of back-up systems that recognize the breaks and repair them." However, researchers have shown that DNA damage repair systems decline as cells age, causing the unrepaired DNA breaks created by Top2 to persist. The unrepaired double strand breaks cause aging, diseases like cancer, and, ultimately, death.
"Many investigators are trying to reverse aging by boosting the backup DNA repair systems in aging cells. A simpler therapeutic approach may be to administer drugs that reduce the activity of enzymes like Top2 that cause DNA damage in the first place." A three- to five-fold reduction in Top2 activity in aging yeast cells resulted in a 20 to 30 percent increase in lifespan.
The lab would not have uncovered Top2's role if it had not first discovered LS1, an unusual Top2 poison. Unlike other Top2 poisons, which are usually highly toxic, LS1 shortens lifespan without affecting the health of young cells. When introduced into yeast cells, LS1 prevents Top2 from repairing its DNA double strand breaks. That's not a problem in young cells with healthy DNA repair systems, but deadly in older cells. However, by transiently stopping Top2 from repairing its own breaks, LS1 enhances the potency of anti-cancer drugs that themselves target Top2 in human cancer cells. For example, the chemotherapy drug doxorubicin causes cardiotoxicity when overused. However, if the potency of doxorubicin were increased by also administering LS1, the same therapeutic affects might be achieved by using less of the drug, reducing the chance of side effects, and extending the utility of these frontline cancer drugs.