Altered cellular communication
Figure 1: Therapeutic approaches for altered cellular communication. Company logo is followed by description of their approach, stage of development, and disease(s) they target.
ECM, inflammaging, immunosenescence, and dysbiosis represent supra-cellular hallmarks of aging, all of which are linked to altered cellular communication. In addition to these, there are various signaling changes within aging that can be generally categorized under the umbrella of altered cellular communication.
Heterochronic parabiosis, a notable example of this hallmark, is an experimental method that involves surgically joining two living animals of different ages to share a circulatory system. First developed in the 1950s, it was later revived in 2005 by Conboy et al., who demonstrated its ability to restore regenerative capacity in the muscles and livers of older mice while adversely affecting younger mice. Several theories have emerged to explain the benefits experienced by the older mice, including the dilution of harmful factors in old blood or the addition of pro-youth factors found in young blood. Although the exact source of these benefits remains uncertain, the technique highlights the principle that systemic factors can influence aging, extending beyond blood factors to include elements such as peptides secreted from mitochondria. Several companies have emerged to develop drugs that add good factors, remove bad factors, or do both.
Another subcategory of altered cellular communication is reproductive aging, in which age-related hormonal changes lead to decline in fertility. These changes not only affect reproductive capacity, but also have broader implications for organismal aging, as evidenced by the occurrence of symptoms associated with menopause. There has been recent interest in this area, giving rise to companies that aim to address aging by targeting reproductive aging.
Adding good factors
1.1. Blood factors
Plasma fractions
Plasma fractions are isolated and purified from blood plasma to contain several therapeutic molecules. Enriched plasma fractions that contain molecules from young blood have the potential to counteract aging-related processes. A 2020 preprint showed that infusing plasma fraction into old rats results in a significant decrease in epigenetic age across the liver, blood, heart, and hypothalamus (Horvath et al. 2020).
Companies have developed proprietary plasma fractions that contain molecules they believe to be beneficial to treat age-related diseases. Alkahest (acquired by Grifols), has developed plasma fraction products for Alzheimer’s and Parkinson’s, which are now being evaluated in phase 2 clinical trials. Yuvan Research is another company developing plasma fractions for age-related diseases.
Specific blood factors
Instead of transferring young plasma fractions into patients, another approach is to identify specific molecules or factors in young blood that can confer regenerative and anti-aging effects. GDF11 is a protein proposed to be a pro-youth factor in young blood (Loffredo et al. 2013, Sinha et al. 2014), though there have been controversy around it due to findings that GDF11 increases with age and inhibits skeletal muscle regeneration (Egerman et al. 2015). Elevian is founded on the GDF11 hypothesis, developing drugs based on the protein to treat age-related diseases. Rejuveron Vascular Therapeutics has also identified molecular targets for neurodegenerative diseases based on parabiosis research, although the targets are undisclosed.
1.2. Klotho
Klotho, also known as alpha-klotho, is a circulating hormone highly expressed in the brain, liver and kidney. Its overexpression has been shown to extend mice lifespan and have neuroprotective effects (Kurosu et al. 2005, Torbus-Paluszczak et al. 2018). Rejuvenate Bio, Unity Biotech, and Klotho Therapeutics are companies working on delivering this protein for aging-related diseases.
1.3. FGF21
Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Its overexpression extends median and maximum lifespan in mice (Zhang et al. 2012).
FGF21 has been a popular target for non-alcoholic steatohepatitis (NASH), an age-related disease where accumulated fat in the liver leads to inflammation and liver damage. Several FGF21 analogs have gone through clinical trials (Shao and Jin 2022). Currently, two clinical-stage companies that are still actively developing FGF21 analogs for NASH are Akero Therapeutics and 89bio.
Rejuvenate Bio is developing FGF21 gene therapy, in combination with TGFβ1 inhibition, to treat aging-related diseases in humans and dogs. Their human programs are still in preclinical stage, whereas their dog programs have entered pilot trials for mitral valve disease, obesity/diabetes, and kidney failure.
1.4. Apelin/APJ
Apelin is a circulating peptide involved in various processes including cardiovascular function, metabolic regulation, angiogenesis, and inflammation. Apelin interacts with its specific G protein-coupled receptor, APJ, which is expressed on the surface of various cell types throughout the body. Apelin/APJ expression is reduced with age (Zhou et al. 2018), and its supplementation reduces age-associated cardiac hypertrophy and sarcopenia in aged mice (Rai et al. 2017, Vinel et al. 2018).
Several companies are working to harness the beneficial effects of apelin by developing APJ agonists as potential treatments for aging-related diseases. BioAge is in a phase 2 trial for muscle aging, APIE Therapeutics targets fibrotic diseases, and Zoe Biosciences is in preclinical development for undisclosed indications.
1.5. Mitochondrial-derived peptides
MOTS-c and humanin are mitochondrial-derived peptides that circulate in the bloodstream and have diverse physiological functions. It has been shown that treatment with MOTS-c significantly improves physical performance in mice across various ages (Reynolds et al. 2021). Similarly, treatment with a humanin analog enhances metabolic health and reduces systemic inflammation in middle-aged mice (Yen et al. 2020). These findings suggest that mitochondrial-derived peptides hold promise as therapeutic targets for aging-related conditions.
CohBar is developing a platform that enables discovery of novel therapeutic mitochondrial-derived peptides. The company is advancing the development of a MOTS-c analog for NASH and obesity. They have also discovered a new peptide, CB5064, and are developing its analog as a potential therapy for fibrotic diseases.
2. Suppressing bad factors
2.1. Blood factors
Plasmapheresis
Plasmapheresis, also known as therapeutic plasma exchange, is a FDA-approved procedure that removes and replaces a patient's blood plasma with a saline solution or albumin. This approach has shown promise in rejuvenating liver, muscle, and brain in old mice (Mehdipour et al. 2020). Lyfspn and IMYu are two companies commercializing this treatment for aging.
Specific blood factors
Another strategy to combat aging-related diseases involves developing inhibitors against detrimental blood factors. Alkahest is advancing this approach by developing products that target eotaxin, a chemokine associated with systemic inflammation in aging-related diseases, and B2M, a pro-aging plasma protein.
Unknown approach
Retro Biosciences is another company developing plasma products for aging. Although their targets are undisclosed, it has been said that the company is inspired by the work of UC Berkeley professors Irina and Michael Conboy, indicating that they are pursuing approaches to remove bad factors.
2.2. TGFβ
The TGFβ superfamily includes the three TGFβ isoforms and other structurally similar proteins with unique biological functions. Abnormal expression of these proteins is associated with various diseases and aging (Tominaga and Suzuki 2019), and inhibiting their activity is a promising therapeutic strategy.
BYOMass, HCW Biologics, and Scholar Rock are developing inhibitors for specific members of this superfamily for various age-related diseases. Rejuvenate Bio is also targeting the inhibition of TGFβ and combining it with gene therapy for other beneficial proteins.
2.3. PAI-1
Plasminogen Activator Inhibitor-1 (PAI-1) is a key mediator of cellular senescence and its genetic deletion extends lifespan in progeroid mice (Vaughan et al. 2017). Zoe Biosciences is developing PAI-1 inhibitors for undisclosed aging indications, while MDI Therapeutics is doing so for fibrosis.
2.4. Other bad factors
Another approach to remove bad blood factors is being developed by a company called Nanotics. They are creating artificial nano-scavengers that can selectively remove pathological molecules from the blood to treat cancer and inflammatory age-related diseases.
3. Unexplored factors
There are various other good and bad factors that have not been explored commercially (Figure 2).
The lists from Rybtsova et al. 2020 and Bieri et al. 2023 suggest potential avenues for further investigation.
4. Reproductive aging
There has always been an interesting link between reproduction and lifespan. For instance, the transplantation of young ovaries into aged, prepubertally ovariectomized mice results in an extended lifespan (Cargill et al. 2003). In human females, menopause onset also serves as a risk factor for age-related diseases.
Some companies are now focusing on enhancing reproductive longevity, which may potentially contribute to overall organismal longevity. Oviva Therapeutics is developing an AMH analog as a new type of contraceptive that prolongs reproductive lifespan, while Gameto is developing a cell-based therapeutic for menopause.