Pathological cells
Figure 1: Therapeutic approaches for pathological cells. Areas with yellow highlight indicate target(s) not explored by existing companies. Company logo is followed by description of their approach, stage of development, and disease(s) they target.
Cellular senescence involves a state of replicative arrest, resistance to apoptosis, and often results in the acquisition of a senescence-associated secretory phenotype (SASP) that is pro-inflammatory and destructive to tissues. These senescent cells tend to accumulate in different tissues with aging. A critical balance of senescent cells is essential as they can aid in wound healing and cancer prevention. However, an excess of these cells can be detrimental, releasing SASP factors that promote inflammation, fibrosis, and cancer development.
Baker et al. (2016) demonstrated that senescent cell removal increased mice median lifespan by more than 35%. Following the publication of this study, there was a surge of interest in the field, with more than a dozen companies emerging to explore the therapeutic potential of senolytics – therapeutics that kill these cells. Nathan Cheng has written a great deep dive into each senolytics company here.
In addition to senescent cells, other harmful cells contribute to aging-related chronic conditions, such as fibrotic cells. Some companies targeting senescent cells are also investigating methods to address these other pathological cells. Consequently, this subcategory encompasses a broader scope than just senescent cells.
Senolytics
1.1. Target anti-apoptotic pathways
Senescent cells are known to be resistant to apoptosis, so one approach for senolytics is to suppress the anti-apoptotic pathways found in these cells.
Bcl-xL inhibition
First-generation senolytic drugs, such as those developed by Unity Biotechnology, repurpose cancer treatments to inhibit anti-apoptotic pathways in senescent cells, particularly Bcl-xL inhibitors.
FOXO4-p53 inhibition
Another anti-apoptotic pathway was identified in a 2017 study that revealed the importance of the FOXO4-p53 interaction in cellular senescence (Baar et al. 2017). Elevated FOXO4 levels are observed in senescent cells, and by disrupting the FOXO4-p53 interaction, apoptosis can be induced. Cleara Biotech and Numeric Biotech are two companies targeting this pathway, both founded by people involved in the paper. Eternans is taking a somewhat different but similar approach in creating a peptide drug that directly binds to FOXO4, instead of to the FOXO4-interaction domain on p53.
HSP90 inhibition
Inhibiting HSP90, a chaperone that stabilizes phosphorylated AKT and protects cells from apoptosis, is another strategy. HSP90 inhibitors were identified as a new class of senolytics recently (Fuhrmann-Stroissnigg et al. 2017), but they have been recognized as an anti-cancer target for several years prior (Gupta and Pan 2020). While many HSP90 antagonists have been discontinued due to issues related to formulation, toxicity, and cost, some are still being tested in clinical trials, primarily for cancer.
It is unclear if any company is specifically developing HSP90 inhibitors as senolytics, and this could be a promising direction.
Natural compounds
High-throughput screening has also identified some natural compounds, approved drugs, and their combinations as effective senolytics. An example is cardiac glycosides, natural compounds that can increase the force of contraction of the heart muscle and regulate heart rate (Triana-Martínez et al. 2020).
Additionally, various combinations and flavonoids have demonstrated the ability to extend the lifespan of mice, including dasatinib (an anticancer drug) + quercetin (a flavonoid), fisetin (a flavonoid), and procyanidin C1 ( a flavonoid) (Xu et al. 2018, Yousefzadeh et al. 2018, Xu et al. 2021). NRTK Biosciences (no website) is currently developing a natural compound analog (fisetin) as a senolytic treatment. ETTA Biotechnology is developing novel molecules based on natural molecule senolytics, including fisetin, quercetin, luteolin, and more. This suggests that developing analogs for other flavonoids (e.g. procyanidin C1) might be a promising strategy.
1.2. gene therapy
Instead of inhibiting anti-apoptotic pathways, another approach is to deliver an exogenous apoptotic gene to senescent cells. Oisin Biotechnologies is a company working on this approach.
1.3. Immune-mediated clearance
Immune-mediated clearance is a technique that involves the activation of the immune system to selectively remove senescent cells. Deciduous Therapeutics employs unique molecules to activate iNKT cells for targeted removal of such cells. Meanwhile, Siwa Therapeutics is developing a monoclonal antibody that targets a glycation marker of senescence, while Starkage Therapeutics also uses immunotherapy for senescent cells removal.
A recent paper from Hasegawa et al. (2023) shows that CD4+ cytotoxic T cells can eliminate senescent fibroblasts, suggesting a potentially new target for senolytic immunotherapy.
1.4. Novel targets
Rejuveron Senescence Therapeutics and Rubedo Life Sciences are two companies using undisclosed novel targets for senescent cells.
2. senomorphics
Another class of drugs for senescent cells are senomorphics, which modulate the phenotypes of senescent cells to prevent detrimental phenotypes without directly killing them. These drugs work by either inhibiting senescence formation, reversing senescent phenotypes, or blocking SASP.
2.1. Inhibit senescence formation
Atropos Therapeutics and Dorian Therapeutics are two companies that are developing drugs to prevent senescence formation through specific proprietary targets.
2.2. Reverse cellular senescence
Senisca is a company that develops drugs that target splicing factors to reverse cellular senescence.
2.3. Blocking SASP
SASP include cytokines, chemokines, and other signaling molecules that are generally inflammatory. Strategies to block SASP overlap with those that target inflammation, which is covered in the “Inflammaging” section.
3. Other pathological cells removal
Senolytics companies have also leveraged their platforms to remove other pathological cells that contribute to aging-related diseases. Oisin Biotechnologies spun out OncoSenX to use their proteo-lipid vehicles for cancer. Similarly, Siwa Therapeutics also applies their immunotherapy platform for senolytics to cancer cells.
Arda Therapeutics is another company that has a focus beyond senescent cells. Through a platform, they are able to identify a range of pathological cells using single-cell data and employ immunotherapies to specifically eliminate these cells. Arda's initial focus is on fibrotic cells, which are known to also increase with aging.