Longevity interventions: Current and future options

 Highlights:

• There are evidence-based interventions available today that can extend lifespan such as rapalogues, and senolytics
• While no human data is available proving that life can be extended at the moment, there are reasons for optimism that what works in model organisms should apply to humans

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Introduction

To be able to extend a healthy lifespan, it is necessary to know the science behind aging research and what growing old implies. While medicine is still far from being able to completely eradicate age-related diseases, some interventions are already available. If translatable to humans from lab data, they could help us age in a healthier way. 

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Evidence-based interventions that promote longevity

The available data that exist on human longevity suggests that exercise and a healthy diet are major factors when it comes to reaching the ages of 80-85, this is when people most commonly die from age-related diseases in highly developed countries. This is why any general practitioner will recommend patients to avoid smoking, follow a healthy diet without too much sugar, and be physically active. These measures doubtlessly reduce rates of premature death and prevent common lifestyle-related diseases. In this case, ‘premature death’ would refer to mortality before about 85-87 years of age, which is the modal age of death in wealthier countries. There are several “longevity hotspots” in the world, such as Okinawa, where people die much less from cancer and coronary heart disease than in the western world (1). While this disease reduction leads to a longer life, it has a modest effect of only a few years compared to the life expectancies in Europe.  

However, there is insufficient data on lifestyle when it comes to reaching extreme ages. For example, some studies show that centenarians do not differ significantly from others regarding weight and smoking habits (2). So, while lifestyle protects people vulnerable to particular life-shortening diseases, gerontologists have a consensus that maximum lifespan is mostly genetically determined in the absence of intervention. 

The field of aging research is far more studied in animals, though, across a wide variety of organisms, there are well-documented interventions that extend life. While data is lacking in humans, there are ongoing clinical trials on some of these compounds, as well as people choosing to self-experiment. 

Options today

An example of an existing intervention that demonstrably extends lifespan across a wide range of species is the drug category of rapalogues. This drug category inhibits mTOR, a central pathway for cellular maintenance, and is currently approved in humans as immunosuppressors (3). The most commonly used rapalogue is Rapamycin (brand name Sirolimus) and there is a broad research interest in using it to improve health in aging humans. However, partially since aging itself is not a disease indication, clinical trials have not been done in humans to see to what extent it could potentially extend life in older people. 

Despite the lack of human data, there are doctors prescribing rapamycin off-label as a therapy for people to self-experiment with in order to potentially live longer and healthier. One example is Dr. Alan Green, a general practitioner in New York area who treats several hundred patients on low-dose rapamycin (4). The benefits that potentially could come from rapamycin apart from longevity include less inflammatory diseases, cancer, as well as fibrosis for organs. 

Next to rapamycin is metformin, known to modulate lifespan across various organisms. It has few side effects and is prescribed as a first-line treatment for diabetics. Since millions of people have taken it for diabetes, there are many human studies. Some data indicates it also has positive effects on preventing heart disease and cancer. Researchers assume that it might slow some mechanism of aging itself, making it a chosen target for the first clinical study on aging in humans (the TAME trial) (5). 

Another aging reversal” area is senolytics, drugs that can eliminate damaged (senescent) cells from the body. Many companies are working on them, and there are already several compounds with documented ability to clear senescent cells from aged mice inducing a partial rejuvenation. Fisetin is an example of a compound accessible for trials and self-experimenting. It is present in strawberries and available at supplement shops without prescription. 

Other substances with these properties include quercetin (also available without a prescription) and the leukemia drug Dasatinib (prescription-only) (6). It is unknown to what extent current senolytics are addressing the problem since there are multiple pathways through with a cell can be in a senescent state. Hence, speculatively a combination of different senolytics would offer the most comprehensive clearance as well as at what ages the interventions are performed (7).

Conclusions on current treatments

In conclusion, while there are many treatments available to slow aging in animals, there is not much human evidence on many interventions yet. That does not mean it would not work, but that the effects so far are unproven. It is up to the individual to make a calculated risk-benefit analysis to self-experiment with these compounds in order to improve health and gamble if they would live longer than their average life expectancy. Concrete examples would be baseline measurements of methylation clocks before and after the interventions.

Options in the future

There is a significant discrepancy between experiments done in the lab and therapies available as conventional medicine for humans in aging research. It is hard to speculate about what therapies will be the most marketable and profitable over the foreseeable future.

However, there are some likely possibilities. For example, as the field of senolytics continues to grow, there could be many competing options available on the market, which may clear different senescent cells from the body in a superior manner.

If one follows the hallmarks of aging as a guide, there are areas where research is closer to implementation: mitochondria, nutrient sensing, and inflammation(8). There are mitochondrial drugs on the verge of clinical trials such as urolithin A for skeletal function and commercially sold offlabel nicotinamide riboside. Furthermore, medications like SS-31 that are currently trialed for muscle myopathy and heart failure may be repurposed for aging. Issues like inflammation and deregulated nutrient sensing, while partially possible to address with anti-inflammatory drugs and metformin, will likely be areas of growth in the future (9).

Another area is stem cell exhaustion, surrounded by the promises of a wider range of stem cell therapies. Much of it has not panned out, and the only FDA-approved use is hematopoietic stem cell transplants. In theory, this is an area where many transformative developments can be made if issues related to tissue engraftment and cell viability can be controlled. This has not stopped unscrupulous clinics from offering stem cell treatments with limited data to back up their claims of being able to cure disease (10).

There are few options available in the areas of problems within proteostasis (protein homeostasis), such as lipofuscin (a fat/protein accumulation inside cells), crosslinks breakers for sugar molecules stiffening collagen, and DNA repairing drugs (to address genome instability). These areas of aging will eventually need to be addressed as well, and there is plenty of preliminary research to potentially build therapies from.

Summary

There are possibilities to already use science-backed knowledge to intervene in aging. Promoting a healthier aging process would be anticipated to have longevity as a side effect. As for upcoming research, some developments can be anticipated in the near future, such as improved senolytics, drugs targeting mitochondrial diseases, and inflammaging. Finally, some areas are largely unmet by current drug development and where speculating about timeframes becomes difficult. For these hallmarks, significant resources need to be allocated, not only for translation but especially for the understanding of basic biology in order to create drugs for proof of concept.  

References

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2. Govindaraju D, Atzmon G, Barzilai N. Genetics, lifestyle and longevity: Lessons from centenarians. Appl Transl Genom. 2015 Feb 4;4:23-32. doi: 10.1016/j.atg.2015.01.001. PMID: 26937346; PMCID: PMC4745363.
3. Walters HE, Cox LS. mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases. Int J Mol Sci. 2018;19(8):2325. Published 2018 Aug 8. doi:10.3390/ijms19082325
4. Rapamycin Treatment for Age Related Diseases (rapamycintherapy.com)
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7. Ellison-Hughes GM. First evidence that senolytics are effective at decreasing senescent cells in humans. EBioMedicine. 2020;56:102473. doi:10.1016/j.ebiom.2019.09.053
8. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217. doi:10.1016/j.cell.2013.05.039
9. Campbell MD, Duan J, Samuelson AT, Gaffrey MJ, Merrihew GE, Egertson JD, Wang L, Bammler TK, Moore RJ, White CC, Kavanagh TJ, Voss JG, Szeto HH, Rabinovitch PS, MacCoss MJ, Qian WJ, Marcinek DJ. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radic Biol Med. 2019 Apr;134:268-281. doi: 10.1016/j.freeradbiomed.2018.12.031. Epub 2018 Dec 28. PMID: 30597195; PMCID: PMC6588449.
10. Murray IR, Chahla J, Frank RM, et al. Rogue stem cell clinics. Bone Joint J. 2020;102-B(2):148-154. doi:10.1302/0301-620X.102B2.BJJ-2019-1104.R1

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