Safer and more effective senescent cell antiaging treatment

In 2001, Aubrey de Grey and colleagues proposed ablation of senescent cells (ApoptoSENS) as the “damage-repair” strategy of choice for zombie cells. The idea was barely mentioned in the scientific literature. It was largely ignored until 2011 when a powerful proof-of-concept study showed that killing these “zombie cells” using a genetically-engineered “suicide switch” substantially rejuvenated a kind of mouse with a mutation that causes them to accumulate an abnormally high level of these cells.

The Mayo Clinic’s James Kirkland and colleagues developed an ingenious drug-discovery strategy that led to the identification of the first two of a new class of “senolytic” drugs. These drugs selectively destroy senescent cells. These zombie cells are barely able to block the “cellular suicide” mechanisms which normally kill them. Senolytic drugs tip the balance in favor of self-destruction.

In the three short years since that initial breakthrough, the progress in ApoptoSENS has been astonishing. Many studies have now shown that ablating senescent cells has sweeping rejuvenative effects. The rejuvenation is wider-ranging than SENS had predicted. Drugs and gene therapies that destroy senescent cells can restore exercise capacity, lung function, and formation of new blood and immune precursor cells of aging mice to nearly their youthful norms.

Senolytic drugs and gene therapies have
* ameliorated the side-effects of chemotherapy drugs in mice and
* prevented or treated mouse models of diseases of aging such as osteoarthritis, fibrotic lung disease, hair loss, primary cancer and its recurrence after chemotherapy, atherosclerosis and age-related diseases of the heart itself— as well as preventing Parkinson’s disease and (very recently) frontotemporal dementia, a kind of cognitive aging driven by intracellular aggregates of tau protein, which are also an important driver of Alzheimer’s dementia.

Normal cells can handle the inhibition of these pathways when not under stress, they still rely on them when damaged or when the local environment turns hostile. The tradeoff is worth it: that the benefits of purging the aging body of senescent cells far outweigh the dangers of a few lost healthy ones. This is true even in the brain (where killing senescent support cells protects neurons in mouse models of diseases of neurodegenerative aging like Parkinson’s disease and tau-driven dementias) and the heart (where heart function in aging mice is improved, likely by eliminating senescent cells left over from fibrotic responses to damage in the aging heart).

It would be better if there were a way of targeting these drugs more specifically to senescent cells, so that healthy cells wouldn’t be dragged through a trial by fire in order to ensure the elimination of their treacherous neighbors.

Best Senescent Cell Marker

The best and most universal sign of senescent cells is the activity of an enzyme called senescence-associated beta-galactosidase, or SA-beta-gal. All cells produce SA-beta-gal in their “cellular recycling centers” (lysosomes), but because senescent cells contain an abnormally high number of these organelles, they also produce very high levels of SA-beta-gal — so much so that its activity can be detected under conditions under which it can’t be detected in normal cells.

SA-beta-gal degrades the sugar galactose (one half of the milk sugar lactose), so scientists exploit the overproduction of the enzyme to detect senescent cells using chemically modified forms of lactose that change color when cleaved by the enzyme. But a few years ago, a group of scientists began to wonder if there was a way to take advantage of this property not just to detect senescent cells, but to selectively release drugs that would destroy them.

Researchers have used silica nanotubes (called mesoporous silica nanoparticles) to deliver anti-senescent cell materials. The nanotubes are closed off with material (GOS- galactooligosaccharide) which can be opened with the enzyme produced by the zombie cells.

If senolytic drugs were packaged up in GOS-MSN (galactooligosaccharide -mesoporous silica nanoparticles)? Existing senolytics expose all cells to their effects, depending on the different metabolic states of senescent and normal cells for their selective killing power. But the selectivity of GOS-MSN particles is different: they work by only releasing their payload of drugs in senescent cells, such that the great majority of normal cells are never exposed to the drugs at all.

And what if rejuvenation biotechnologists took advantage of the strengths of both of these approaches, by loading GOS-MSN ( galactooligosaccharide -mesoporous silica nanoparticles) with senolytic drugs instead of a generically toxic drug like doxorubicin? You’d expect that this would create a therapy “doubly-selective” for senescent cells: normal cells would almost never be exposed to the drug in the first place — and on the rare occasions when they were, most healthy cells would still escape unscathed, because of the drugs’ intrinsic selectivity for senescent cells.

Drs. Murguía, Martínez-Máñez, and Serrano have launched a biotech startup to turn GOS-MSN into a human rejuvenation biotechnology. Senolytic Therapeutics (Senolytx) projects that “Designed therapies will be efficacious in treating multiple disorders which are caused and driven by the accumulation of damaged cells.

ApoptoSENS type therapies could well be a significant milestone on the road to comprehensive human rejuvenation. ApoptoSENS therapies could treat certain many cancers, diabetes, arthritis, heart disease and more.