Starting with longevity medicine for medical practitioners

‍Highlights:

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• Longevity medicine refers to applying evidence-based science to intervene in the development of age-related diseases in humans
• The field is under development since research is evolving. More research and clinical trials  needed to create actionable therapies
• To optimize longevity medicine, reliable and robust biomarkers of aging are necessary, encompassing proteomic, epigenetic as well as physiological data 

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Introduction

The area of aging research has seen rapid advancements thanks to scientific advancements during the past decades. The aging process has been categorized and divided into subcategories of age-related changes. One of the most famous papers in the field is the work of López-Otín from 2013 on the hallmarks of aging, which divides the aging process into nine categories of dysfunction (1). By breaking down our current understanding of aging, we now have unprecedented amounts of data on the topic to draw upon and implement new interventions.

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Background

What can be done today in order to extend the healthy lifespan of humans? Historically medical intervention has been reserved mostly for people who displayed clinical symptoms. This has changed when preventive medicine has emerged, embodying a paradigm shift where one intervenes pharmaceutically in a generally healthy person to prevent future diseases.

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 There are three types of prevention:

• Primary - refers to preventing any disease before it occurs, e.g., vaccination
• Secondary -  regular screenings of patients who could be at risk for diseases, such as cancer
• Tertiary - the rehabilitation of existing diseases (2)

This needs further development since, according to statistics, less than 3% of healthcare expenditure is spent on preventive approaches (3). Conventional advice such as stopping smoking, keeping a normal weight, and exercising more have for a long time been given to patients and perceived as preventive medicine. However, prescribing pharmaceutical drugs for prevention, as well as screening for aging-specific problems before symptoms appear, is an emerging trend. This is being facilitated since medical researchers have more advanced tools at their disposal compared to the past.

The field of measuring human aging biomarkers is growing; life-extending compounds that have been shown to work in lab animals are being discovered and categorized (4). These compounds are also undergoing trials in humans. There is an increased understanding that to prevent multiple age-related diseases one must intervene in the aging process (5). Multiple clinics now offer state-of-the-art diagnostic screening to discover diseases early - examples include Grossman Wellness Center in the United States.

Specific challenges for practicing longevity medicine

• Lack of evidence and human data

Since aging research has grown dramatically during the past couple of decades, there is more experimental data on therapies to implement in humans. There is also a better understanding of the biomarkers that characterize human health. These biomarkers can be both physiological measuring clinical organ function or molecular markers that can be obtained from blood plasma. While the developments are encouraging, there is still a lack of knowledge in translating lab findings into humans, which means that longevity medicine is still, in many ways, a grey area (6). Often the tests that measure aging are still in the experimental stage, for example, epigenetic clocks. There are several different companies in this area with technologies that offer consumers epigenetic tests measuring how well they are aging (7,8). These tests are based on reliable science measuring human epigenetic markers in different ages and disease conditions. However, it should be noted that they are still experimental in the sense of not being approved by the FDA or incontrovertibly shown to accurately predict disease in an individual. 

• Regulatory Aspects 

Another thing to keep in mind when practicing longevity medicine is the legislation. Laws regulating what therapies a doctor can administer to a patient are strongly different from country to country. There is an industry aimed at circumventing those laws, the so-called offshore medical tourism sector. It has become a viable option for customers willing to gamble on therapies. It is now a significant sector and offers many treatments that are not approved in the US and Europe.

As for the aging market field, examples are stem cell treatments for various disorders. These treatments are often not well controlled and built on experimental data, which implies health risks for patients (9). Since aging is not considered a disease, one cannot run a clinical trial on aging for a drug but have to find ways to find surrogate endpoints. This means that patients also may seek out experimental procedures in countries where it is allowed. Examples of companies operating in this area include Bioviva and Libella, which use telomere extension therapies that could potentially impact aging, and many offshore stem cell clinics (10). These are treatments that are not fully tested but are still in an experimental state, lacking completed clinical trials and approval. 

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Developments in the area

Longevity medicine strongly overlaps with the established area of precision medicine, where individual patient data is gathered to optimize treatments. A useful tool in this area is the use of artificial intelligence in order to more rapidly screen for disease risks and do basic research to develop a better understanding of multi-omic patient data. More data is available on what constitutes aging which means more potential therapies can be developed from the discovery phase to gradually be implemented (11). Any aging biomarker needs to be predictive and tied to a specific physiological function that can be improved upon by a therapy. For example, if improving an aging biomarker does not generate a health benefit, it may indicate a compensatory response rather than that the treatment has improved an aspect of aging.

Another problem is that aging is multifactorial, so a practicing physician may need to prescribe combinatorial therapies. This would address multiple aspects of aging in a patient to generate a positive health outcome, which increases the risk of possible side effects. 

A physician practicing longevity medicine would need to stay up to date with new scientific studies and clinical trials to make the best reasonable judgments to maximize the healthspan and lifespan of patients while avoiding serious side effects. 

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Advancing diagnostic and treatment opportunities

There are studies on longevity compounds, for example, the Participatory Evaluation of Aging with Rapamycin for Longevity study (PEARL) conducted by UCLA. This is an example of a clinical study on aging in humans that has a rationale based on lab data; it measures multiple parameters of health such as bone health, kidney function as well as adverse outcomes during a four-year period. It is conducted on middle-aged to younger elderly aged 50 to 85 and estimated to be completed by the end of 2023 (12).

A second area is the area of senolytics, drugs removing senescent (damaged) cells from tissues. This rejuvenation method has a large body of research behind it since older organisms accumulate these damaged cells. There are ongoing human trials with positive results for specific conditions, where senescent cells are prevalent, such as idiopathic pulmonary fibrosis (13). In the case of senolytics, it should be noted that having this particular form of aging damage is not seen as a disease in itself. This means that it is necessary to target specific diseases rather than the systemic accumulation of senescent cells inevitably seen in a population due to aging. 

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Summary

The area of longevity medicine encompasses biomarkers of aging, implementing and assessing longevity interventions from lab data, and monitoring efficacy by the treating physician. Some actionable tips to start longevity medicine are:

• Thoroughly understanding the biomarkers of a patient: Do comprehensive physiological testing and multi-omic data to quantify aging.
• Awareness of the currently available drugs/supplements that can help slow aging.
• Diligently paying attention to the constantly evolving area of aging research and how these may be incorporated into a treatment plan.

Being a longevity physician means having the medical knowledge of traditional medicine and, through scientific guidance, implementing the advances of aging research into living human beings. This is not an easy feat since one needs to understand the risks of potential regenerative treatments, while balancing them with the risk of choosing not to undergo them. Currently, there is a large discrepancy between what has been demonstrated in the lab and what has been implemented in humans. Furthermore, the time to develop medicine is very long, meaning informed patients are likely to push for experimental treatments to age better. These are all challenges the physician wishing to practice longevity medicine is facing, and to achieve the best results, information is key. 

References

1. 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
2. WHO/Europe | Public health services - EPHO5: Disease prevention, including early detection of illness
3. OECD Health Statistics 2021 - OECD
4. Moskalev, Alexey et al. “Geroprotectors: A Unified Concept and Screening Approaches.” Aging and disease vol. 8,3 354-363. 2 May. 2017, doi:10.14336/AD.2016.1022
5. Kaeberlein M, Rabinovitch PS, Martin GM. Healthy aging: The ultimate preventative medicine. Science. 2015;350(6265):1191-1193. doi:10.1126/science.aad3267
6. Bell, C.G., Lowe, R., Adams, P.D. et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol 20, 249 (2019). https://doi.org/10.1186/s13059-019-1824-y
7. Zymo Research Receives Exclusive Licensing Agreement for Dr. Steve Horvath's Epigenetic Aging Clock Technology | UCLA Biostatistics
8. https://www.sec.gov/Archives/edgar/data/1812360/000121390022009297/ea156134ex99-3_delwindsacq.htm
9. Samantha Lyons, Shival Salgaonkar, Gerard T Flaherty, International stem cell tourism: a critical literature review and evidence-based recommendations, International Health, Volume 14, Issue 2, March 2022, Pages 132–141, https://doi.org/10.1093/inthealth/ihab050
10. Evaluation of Safety and Tolerability of Libella Gene Therapy for the Treatment of Aging: AAV- hTERT - Full Text View - ClinicalTrials.gov
11. Zhavoronkov, A., Bischof, E. & Lee, KF. Artificial intelligence in longevity medicine. Nat Aging 1, 5–7 (2021). https://doi.org/10.1038/s43587-020-00020-4
12. Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov
13. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-563. doi: 10.1016/j.ebiom.2018.12.052. Epub 2019 Jan 5. PMID: 30616998; PMCID: PMC6412088.

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