SENS Research Foundation 2023 Annual Report

The SENS Research Foundation has released its 2023 annual report. This is one of the few non-profit organizations focused on advancing the state of research and development of rejuvenation therapies. It exists in the same family tree as the Methuselah Foundation and LEV Foundation, and all three now have somewhat different areas of focus within the same broad outline. In comparison to the SENS Research Foundation, the Methuselah Foundation gives more attention to tissue engineering, while LEV Foundation is presently investigating combinations of potential rejuvenation therapies in animal models, a sorely neglected area of research.

The SENS Research Foundation works on a number of interesting projects that might lead to rejuvenation therapies, and the focus remains to unblock promising lines of research that are underfunded, poorly investigated due to a lack of tooling, or otherwise neglected by the research mainstream. The foundation also holds stakes in a range of companies formed to develop programs that SENS Research Foundation was in some way involved in, either conducting, funding, or otherwise assisting in moving that research forward. These include Cyclarity Therapeutics and Repair Biotechnologies, both focused on atherosclerosis, as well as ventures tackling senescent cells, cross-links, and other aspects of aging biology.

Looking at the 2023 report, it is fair to say that the SENS Research Foundation's fundraising has suffered this past year, following the departure of co-founder Aubrey de Grey to form the LEV Foundation. One could argue that this has more to do with the current market downturn, of course. Non-profits tend to do poorly as the market falters. The foundation has a fair-sized war chest, but they can't keep up the present pace on present research programs without increased support from philanthropic donors. This organization does good work; it is a worthy cause that this community has supported well in the past, and should continue to support in the future.

SENS Research Foundation Annual Reports

SRF's ApoptoSENS team are developing ways to target senescent cells that evade existing senolytic strategies while reducing damage to healthy cells. One blind spot in the senolytic story has been the effects of these drugs on "secondary senescent cells." Secondary senescence is a more recently-discovered and understudied form of senescence that occurs when cells are driven into senescence by the signaling molecules released by other cells that had previously become senescent (the "primary" senescent cells). SRF scientists wondered if they might elude many of our existing senolytic drugs, since all such drugs were developed by testing them against primary senescent cells. Sure enough, secondary senescent cells could shrug off several of the best-studied senolytic drugs.

Fortunately, SRF scientists found a novel route of senolytic attack that works well against both types of senescence. These cells intensively engage pathways involved in iron metabolism, and also seem to be primed for ferroptosis, a kind of programmed cell death that depends in part on iron as a trigger. The ApoptoSENS team found that both primary and secondary senescent cells are susceptible to novel attack routes that exploit pain points along this pathway.

Senolytics - senescent cell-destroying drugs - are now one of the most rapidly-advancing rejuvenation biotechnologies. Unfortunately, these drugs do inflict some collateral damage to nonsenescent cells. So how much better might senolytics work if SRF scientists coupled them with strategies to enhance the aging body's flagging regenerative response after treatment? The SenoStem group is preparing to test just such a combination. This team will seek to fortify surviving nonsenescent cells with pro-regenerative signaling factors from mesenchymal stem cells (MSCs).

SRF's MitoSENS team is now working on three ways to deal with mitochondria that bear large deletion mutations. The first approach, which they've been working on since SRF's founding, entails creating "backup copies" of the mitochondrial genes in the nucleus. The team's standout success with the gene ATP8 enabled an engineered backup copy of this gene to express in living mice. Other genes are proving harder to engineer such that their proteins are reliably produced, delivered, and correctly placed in the energy- production machinery. The MitoSENS team is working to overcome the tendency that some mitochondrial proteins have to curl up on themselves.

The MitoSENS team is also in the early stages of working on two alternative strategies. One is a version of a "gene drive," using therapeutic mitochondria engineered with an enzyme that can destroy all the existing mitochondrial genomes in the cell. Once transplanted into an aging patient, these aggressive mitochondria would enter the patient's cells and replicate themselves while buzzsawing through the existing mitochondrial population, replenishing the cell with pristine, functional mitochondria. The other strategy aims to overcome the culling-avoidance superpower of mitochondria that bear large deletions in their genome. The team is testing several different drugs that may be able to force deletion-bearing mitochondria to show their faces and be marked for destruction by the cell maintenance process of mitophagy.

SRF's LysoSENS team is working on an ingenious strategy to clear aging neurons of tau oligomers. Their strategy consists of two major components: a novel cell- penetrating platform to deliver their therapeutic antibody inside the neurons, and the use of catabodies instead of conventional binding antibodies to attack their target. Catabodies, unlike conventional antibodies, cleave their targets into harmless fragments, rather than dragging intact target aggregates one by one out of the brain (and in doing so, damaging the brain's blood vessel barrier). The LysoSENS team is developing both a suite of potential catabodies to test and synthetic tau oligomers against which to test them, to ensure that catabodies that successfully buzz their way through the artificial target will also obliterate the real enemy inside the neuron. When they are satisfied with the oligomers, they will begin testing catabody candidates, and after that move on to studies in cells and in mouse models of tau-driven neurodegenerative aging.

Scientists have been pursuing a way to clear aging cells of lipofuscin for longer than any other LysoSENS target. Past efforts have failed in part because real lipofuscin is hard to isolate from cells, forcing scientists to resort to artificial mixtures of crosslinked materials or a lipofuscin-like material produced by cells under abnormal conditions. With SRF funding, researchers are now attacking the problem using new techniques to isolate true lipofuscin derived from human donor and horse heart tissue. Horse and human heart lipofuscin are very similar, allowing them to work with the larger available quantities of horse material with confidence that the results will also apply to human lipofuscin. The team is now attacking this isolated lipofuscin using the classic LysoSENS strategy of screening environmental bacteria for the ability to survive by breaking it down. Excitingly, their mixed soil bacterial population can degrade lipofuscin and release fluorescent breakdown products. They are now winnowing this population down to determine which species produce the enzymes that do the critical work.

One key change in aging extracellular matrix (ECM) is crosslinking, in which one strand of a structural protein becomes chemically bound to an adjacent strand, limiting both strands' range of motion. Continuous exposure to blood sugar and other essential but highly reactive molecules in the blood can lead to a kind of crosslink termed Advanced Glycation Endproducts (AGE). The evidence currently suggests that the single most common AGE crosslink in the key structural protein collagen is glucosepane. SRF funded research has now shown that each kind of tissue undergoes its own distinct crosslinking pattern, and the crosslinks that form don't simply accumulate over time as was previously believed. Instead, a subset of crosslinks easily breaks during regular tissue stretching, only for new crosslinks of the same type to form afterward.

In fact, while researchers have confirmed that irreversible crosslinks increase in aging tendons with age, this increase is more than counterbalanced by a net loss of the reversible crosslinks, which may contribute to putting us at greater risk of rupturing our tendons as we age. Moreover, while the team has confirmed that the age-related rise in glucosepane seen in human tissues also occurs in mice, there's no sign of some of the other crosslinks previously reported in either species. This careful work is showing that some of these are instead either methodological artifacts or cases of misidentification.