In the longevity space, there is a search for ways to extend lifespan or at least improve the quality of life in later years. One way biotechnology is poised to make this possible is through the development of senotherapeutics, drugs that target cellular senescence or cell aging.

Insights from advances like regenerative therapies, precision medicine, and high-throughput omics are pushing research into senotherapeutic drug discovery and screening. However, there is a major bottleneck. “We don't know how aging works,” said Martin Borch Jensen, CSO of San Francisco-based Gordian Biotechnology. We also don't know whether models of aging are capturing the essence of aging biology.”

Screening Senotherapeutic Targets

Senotherapeutic drug development is significantly different from conventional drug development. Usually, the diseased cells proliferate. With oncology drugs, for example, the challenge is to selectively eliminate uncontrollably growing tumor cells. “The senescence cell field flips that problem on its head,” said Alex Colville, general partner at longevity biotech-focused venture capital firm age1. “How can we eliminate the cells that are dividing the least and are in this semi-permanent cell cycle arrest?”

Tackling this challenge requires deep insights into different senescent and senescent-like phenotypes and the mechanisms that lead to them. Artificial intelligence and machine learning models provide a way to discover mechanisms and interaction networks from biological data. The field needs better data to plug into these models, and high-throughput screens are addressing this gap. 

A lack of naturally aged animals often limits aging studies. Gordian overcomes this with its pooled in vivo screening technology, which looks at thousands of targets in a single animal. It delivers a pool of different barcode-tagged therapies at low doses to create a mosaic organ in which a few cells have received some therapy, whereas others are not perturbed.

“We sequence all cells, and that gives us the gene expression in the cells as well as the identity of the therapeutic that was in the cells,” Jensen explained. “You can then split them into pools of cells that have one or the other therapeutic and compare what happened.” This allows for predictive modeling of the physiological changes happening in the cells.

UK startup clock.bio, on the other hand, uses unbiased CRISPR screens, a technique to tweak all genes to see what changes systematically. According to CEO Markus Gstöttner, “clock.bio aims to extend and improve quality of life by reversing the harmful effects of time in our cells, harnessing the regenerative capabilities of human-induced pluripotent stem cells (hiPSCs).”

The startup’s technology temporarily ages these cells, and they start exhibiting cellular hallmarks of aging. “This triggers a self-rejuvenation mechanism in hiPSCs that allows them to undo aging damage within a couple of weeks,” said Gstöttner. CRISPR screens then reveal the genes driving the rejuvenation process in the cells.

Gstöttner added that “understanding of repair or rejuvenation biology and how rejuvenation targets relate to individuals, or combinations of aging hallmarks, allows the design of treatment strategies for age-related conditions.”

‍

Approaches to Target Cellular Senescence

In many tissues, populations of senescent cells are essential for repair and regeneration. Moreover, many terminally differentiated cells, like neurons and heart muscle cells, have senescent-like features. “We don't have a clear understanding of which cells, in vivo in humans, are important to remove selectively,” said Colville. Distinguishing aged and senescent cells from healthy cells remains a priority of research in the field. 

Senotherapeutics can be broadly classified into senolytics or senomorphics. While the former induces cell death in senescent cells, the latter suppresses the effects of cellular senescence. Senolytics dominate the senotherapeutics landscape, mainly due to the effectiveness of small molecule drugs at killing cells.

No senotherapeutic drug has been approved yet, but they have shown promise in preclinical trials in different organ systems. These include drugs approved for other conditions, such as the FDA-approved leukemia treatment dasatinib. Combined with the nutraceutical quercetin, dubbed D +Q, it has been shown to alleviate age-related metabolic dysfunction in mice. 

Approaches to improving the action of senotherapeutics focus on selective delivery to senescent cells. “These include pro-drugs that go into senescent cells and are then activated to become the actual activated ingredient and have the desired effect in only senescent cells," said Colville.

Immune cell-based therapies also selectively target senescent cells based on their surface markers. San Francisco-based biotech Deciduous Therapeutics leverages natural killer T (NKT) cells’ endogenous ability to clear senescent cells. The company’s CEO, Robin Mansukhani, said, “You eliminate off-target effects by having a drug that binds specifically to an NKT cell.”

People with obesity or metabolic diseases have a suppressed immune function similar to that due to aging. When those diseases are treated, the immune function normalizes and becomes more effective. Conversely, “if you restore the immune function, that also treats obesity and other metabolic diseases,” added Mansukhani. This shows that developing anti-aging drugs could also open up new therapeutic targets for other diseases.

‍

Cancers and Other Aging-Associated Diseases

Like with immune function, aging has a bidirectional link with other aging-associated conditions. For example, not only does the risk of developing cancer go up with old age, but cancer and cancer treatments also accelerate aging. This is why, in addition to repurposing cancer drugs as anti-aging drugs, researchers are also looking to develop senotherapies for cancer treatment.

Longevity biotech companies focus on different aging-associated diseases. Gordian is working on heart failure with preserved ejection fraction, osteoarthritis, and pulmonary fibrosis. Deciduous Therapeutics is focused on pulmonary fibrosis and metabolic disease.

However, senotherapeutic drug discovery could also benefit from a holistic approach to studying aging. “We focus on organs one at a time. We're not changing the pancreas and then looking at what happens in the liver,” said Jensen. Combining information from multiple screens and real-world data could yield useful insights into aging biology.

While some senotherapeutic interventions might be effective for most senescent cells, others could act in a cell-type-dependent manner. Jensen contrasted fibrosis and osteoarthritis, both age-associated diseases, as an example. Meanwhile, fibrosis is marked by collagen build-up in the lung, while knee joints lack collagen in osteoarthritis.

Cellular senescence is intricately linked with other hallmarks of aging, such as mitochondrial dysfunction and epigenetic alterations. This is why a 2022 review in The Journal of Clinical Investigation posited, “Combining senotherapeutics with geroprotective interventions may provide additive or synergistic therapeutic effects in aging and diseases.” Better in vivo models of diseases and aging will also advance senotherapeutics and anti-aging interventions more broadly.