Strike (aging) when the iron is hot

As we age, our bodies accumulate damaged “senescent” cells that spread inflammation in our bodies and drive us into age-related disease and debility. Destroying these senescent cells with drugs called senolytics is an exciting pathway toward keeping us in youthful health for longer. SENS Research Foundation scientists have now discovered that a key population of senescent cells resists existing senolytic drugs. But both these and the better-known types of senescent cells share a key vulnerability, and a new class of broad-spectrum senolytic drug that targets this vulnerability executes senescent cells that other senolytics pass by.

The results are published in the journal Cell Reports.

One of the ways that senescent cells spread destruction in aging tissues is to secrete factors that turn healthy neighboring cells senescent. Until now, scientists had thought that the “secondary senescent” cells created by this process were a dead end, unable to seed more senescent cells in turn.

But SENS Research Foundation’s Dr. Tesfahun (Tes) Admasu noted that the way that scientists had tested secondary senescent cells’ ability to drive even more cells into senescence artificially diluted their secretions and thus underestimated their pernicious potential. By developing a new way to collect secondary senescent cells, he was able to show that they are just as effective at turning their neighbors senescent as the “primary senescent” cells that originally drive them into the state. This underestimated ability creates the potential for a ruinous domino effect in aging tissues.

Worse: in testing how secondary senescent cells might differ from their predecessor cells, Dr. Admasu discovered that secondary senescent cells develop alternative survival strategies from the ones used by primary senescent cells to keep themselves alive. Because they don’t require the survival pathways that other senescent cells lean on, secondary senescent cells resist many of the established senolytic drugs that are known to destroy primary senescent cells.

Digging in, Dr. Admasu found that many metabolic pathways activated in secondary senescent cells involve abnormal iron metabolism. That helped explain why senescent cells have high levels of highly reactive unbound iron inside them—something other researchers had previously highlighted.

This discovery opened up two new ways to destroy secondary senescent cells. One is to use drugs that inhibit key processes that senescent cells use to survive in the face of internal forces that press them into “ferroptosis” — a form of programmed cell death triggered by the very iron they hoard. Another is to use “cage” molecules that lock up cell-killing drugs inside their structure and only release their payload in when high levels of reactive unbound iron are present. These drugs pass harmlessly through normal cells, because reactive iron levels are low. But when they enter senescent cells, the high level of reactive unbound iron unlocks the “cage” molecule, which releases its deadly payload and destroys the senescent cell.

Better yet, both ferroptosis-activating drugs and the reactive iron-activated “caged” drugs are effective against both primary and secondary senescent cells, making them the broadest-acting senolytics known.

“When I joined SRF, the first question I asked myself was how to overcome the two major hurdles holding back our ability to target senescent cells: the diversity of senescent cell phenotypes and the problems with current senolytics,” says Dr. Admasu. “Our labile iron-activatable prodrug is an important milestone in the field of senolytic drug discovery because it is a novel and broad-spectrum senolytic approach that avoids the non-specific toxicity of other senolytics.”

Dr. Sharma adds, “Our results have shed new light on how exposure to senescent cell secretions can itself drive senescence, and how the resulting secondary senescent cells differ from primary senescent cells. Importantly, our work shows that secondary senescent cells are resistant to several current senolytics, and a new way to target all types of senescent cells based on their labile iron load. We are now testing the therapeutic potential of this approach in animal models of diseases of aging.”

SENS Research Foundation is a 501(c)3 biomedical research therapy that develops longevity therapeutics that directly remove, repair, and replace the cellular and molecular damage of aging, with the aim to extend the youthful, healthy human life.

Admasu TD, Kim K, Rae M, Avelar R, Gonciarz RL, Rebbaa A, Pedro de Magalhães J, Renslo AR, Stolzing A, Sharma A. Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis. Cell Rep. 2023 Feb 6;42(2):112058. doi: 10.1016/j.celrep.2023.112058. PMID: 36753419.