Fight Aging!

Today, I'll point out an analysis from the SENS Research Foundation that covers the approach to selective destruction of senescent cells taken by one of the newly formed biotech startups in the space, Senolytic Therapeutics. This field is hot because it is now well proven that senescent cells are the enemy. They are one of the root causes of aging, accumulating with age to degrade tissue function via the secretion of inflammatory signal molecules. Senescent cells actively maintain an aged, inflamed state of metabolism, resulting in the development of age-related disease and increased mortality.

Senescent cells do serve useful functions when they arise temporarily in response to injury or cell damage, so senescence as a phenomenon cannot be safely suppressed. Since the problems only begin when these cells both fail to self-destruct and evade the immune system's policing of tissues, however, finding ways to periodically destroy all lingering senescent cells is a very viable approach to rejuvenation. When they are removed from old tissues, aged metabolism is quite quickly restored to an incrementally younger state. This point has been quite adequately demonstrated in mice in recent years.

Roughly speaking, there are two approaches to the selective destruction of senescent cells. The first approach is to target a mechanism that is only significant in senescent cells, such as the fact that they are primed for self-destruction via apoptosis, and only held back by the thinnest of threads. A nudge to the apoptotic protein machinery that a normal cell will ignore will tip a senescent cell over the edge. The present crowd of senolytic pharmaceuticals fall into this category. The second approach is to use a therapeutic that will definitely kill any cell, senescent or not, and then limit its application to senescent cells only. Forms of immunotherapy and suicide gene therapy currently under development are examples of the type.

The staff at Senolytic Therapeutics are undertaking an interesting approach to the delivery of a standard chemotherapeutic means of killing cells in which nanotubes are used to ensure that only senescent cells are exposed to the toxin. The hollow nanotubes are filled with chemotherapeutic and capped with a molecule that only senescent cells will remove. Or at least only cells that express large amounts of senescence-associated beta-galactosidase, which might not be exactly the same thing, but the overlap is quite large. This is similar to a wide variety of approaches to targeting of specific cell populations developed in the cancer research community, and most of those are probably also applicable in principle to the task of clearing senescent cells from old tissues.

Smart Bombs Against Senescent Cells

When Dr. de Grey and colleagues proposed ablation of senescent cells (ApoptoSENS) as the "damage-repair" strategy of choice for this kind of aging damage in 2001, you'd've been hard-pressed to find the idea even mentioned (let alone advocated) in the scientific literature - and certainly no one was actively working to develop such therapies. This approach remained largely ignored until a powerful proof-of-concept study in 2011. Soon after that, researchers developed an ingenious drug-discovery strategy that led to the identification of the first two of a new class of "senolytic" drugs - that is, drugs that selectively destroy senescent cells.

In the three short years since the initial breakthrough discovery of the first senolytic drugs, the progress in ApoptoSENS has been astonishing. A torrent of scientific reports have now shown that ablating senescent cells has sweeping rejuvenative effects - wider-ranging, in fact, than we ourselves 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 also 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.

Scientists use a range of different cell markers to identify senescent cells: no one marker is infallible, and different senescence markers are more dominant in different senescent cell types. But the best-established and perhaps most universal sign of all is the activity of an enzyme called senescence-associated beta-galactosidase, or SA-beta-gal. To create a system that would release of cell-destroying drugs selectively in cells with senescent-cell levels of SA-beta-gal, chemists and nanotechnologists turned to an established platform for the selective delivery of drugs: mesoporous silica nanotubes, or MSNs. What makes MSNs so useful as drug-delivery systems is that their constituent tubes can be packed with any number of different drugs, and their openings on the surface of the nano-balls "capped" with molecular stoppers that keep the drug sealed inside until the MSN encounters chemical or other conditions that can break open the seal. So the trick is to identify a molecular stopper that is sensitive to chemical or physical conditions that are found in the type of cell that you want to target, and not found in innocent cells that you want to leave alone.

SA-beta-gal's actual function in the cell is to breaks down the sugar galactose: senescent cells just produce a whole lot more of it than normal cells. So to target MSNs to senescent cells, the team used galactooligosaccharide (GOS) as the stopper molecule - that is, a series of galactose molecules strung together in a chain. The researchers predicted that with their overabundance of SA-beta-gal, senescent cells would whittle down the chain of galactose molecules until they uncapped the MSNs and released their payload, while the same MSNs would pass through normal cells with their contents still safely sealed up. To test this, the team first drove several lines of cancer cells senescent using palbociclib, a cancer drug that works by shutting down genes that cancer cells require for cell division. They loaded up their GOS-MSN with doxorubicin, a toxic chemotherapy drug that is lethal to normal, cancerous, and senescent cells alike. An additional useful feature of doxorubicin is that it's intrinsically fluorescent, allowing the scientists to easily see where it was released.

GOS-MSN loaded with doxorubicin (DOX-GOS-MSN) passed harmlessly through three non-senescent cancer cell lines, and only released their payload in a small percentage of cells of the same lines that were exposed to palbociclib too briefly to induce widespread senescence. But when cancer cells were exposed to palbociclib for long enough to force them into senescence en masse, they lit up with doxorubicin fluorescence, and programmed cell death raged through the population.

Previous research had already shown that a variety of ApoptoSENS strategies can prevent or reverse idiopathic pulmonary fibrosis (IPF) in mouse models of the disease, as well as reversing the "normal" loss of lung function with age. The team wanted to see if DOX-GOS-MSN could similarly restore lung function in mice with a model of IPF. After first confirming that GOS-MSN distributed evenly across normal and senescent lung tissue they treated mice with either straight doxorubicin or DOX-GOS-MSN for two weeks, starting two weeks after inducing model IPF. Lung dysfunction scores remained stubbornly high in animals treated with plain doxorubicin, but DOX-GOS-MSN restored the lung function of the IPF model mice levels equivalent to young mice not subjected to lung damage. DOX-GOS-MSN also reduced the amount of fibrotic tissue in the animals' lungs, which untargeted doxorubicin was again unable to do.

With those exciting results in hand, the researchers have launched a biotech startup to turn GOS-MSN into a human rejuvenation biotechnology. Senolytic Therapeutics projects that that their therapies will be efficacious in treating multiple disorders which are caused and driven by the accumulation of damaged cells - that is, exactly the conditions that GOS-MSN treated so successfully in their recent proof-of-concept scientific report.