Table of Contents
- Key Points
- Aging as a Risk Factor for COVID-19 and Other Infections
- What Is Geroscience?
- Immune Dysfunction and Inflammaging: The Aging Immune System
- What Can We Do Today?
- Geroprotectors: Existing Drugs That Target Aging
- The Need to Advance Gerotherapeutics Now
- Biotech and the Drug Pipeline
- A Geroscience Approach Would Benefit Not Only the Chronologically Old
- Strategic Research Directions: Evaluation of Aging, Multimorbidity, and Frailty
- Policy Implications: Lessons From the Pandemic
- What This Means for Patients
- Frequently Asked Questions
- Source Information
Key Points
- Older adults are most vulnerable to COVID-19; 77% of US deaths were people aged 65+ as of April 2020.
- Geroscience targets aging biology to delay or prevent multiple age-related diseases, including infectious disease risk.
- Metformin use was tied to lower mortality in Wuhan COVID-19 patients with diabetes: 2.9% vs. 12.3%.
- Lifestyle measures such as good nutrition, exercise, stress management, and sleep support immune function.
- Do not self-medicate with metformin or rapamycin; these are experimental geroprotectors needing clinical trials.
Aging as a Risk Factor for COVID-19 and Other Infections
The data on COVID-19 is painfully clear on at least one point: older adults are the most vulnerable to hospitalization, disability, and death following infection with the novel coronavirus. As of April 2020, the Centers for Disease Control and Prevention (CDC) reported that 77% of all COVID-19 deaths in the United States were people aged 65 and older.
The age-related risk is staggering. Among those infected, people aged 80 and older die at a rate that is 200 times higher than someone in their 20s. This vulnerability to infection is not new. Even before COVID-19, the risk of death attributed to pneumonia increased about 1,000-fold between ages 25 and 85.
This pattern means that the problem is not simply the virus itself, but the aging of the body that makes it so vulnerable. That is why the authors argue that a geroscience approach — targeting the aging process directly — is expected to be relevant not just for this pandemic, but for future infections, epidemics, and pandemics we have yet to face.
What Is Geroscience?
Geroscience is a scientific field supported by the National Institute on Aging (NIA) and other organizations that seeks to understand how the biology of aging drives age-related diseases. The central idea is that aging itself is the greatest risk factor for most chronic diseases, so modifying the aging process could delay, prevent, or treat multiple diseases all at once.
Geroscientists have long hypothesized that by targeting the biology of aging, all diseases of aging can be delayed. This is based on a well-established framework called the "hallmarks of aging" — a set of interconnected biological processes that include genomic instability, cellular senescence, mitochondrial dysfunction, and others. These hallmarks are all connected, so targeting just one hallmark often results in improvements in the others.
In animal studies, researchers have dramatically increased both health span (the years of life spent in good health) and life span by targeting these hallmarks with genetic tools and drugs such as metformin and rapamycin. This demonstrates that aging is a modifiable condition, not an unchangeable fate.
Immune Dysfunction and Inflammaging: The Aging Immune System
Of particular importance in the COVID-19 pandemic are two aging-related changes that underlie the vulnerability of older adults to infections. The first is immunosenescence — the gradual weakening of the immune system as we age, which makes it harder to fight off new infections. The second is inflammaging — a state of chronic, low-grade inflammation that develops with age and can produce an excessive and harmful inflammatory response to an infection.
But the authors emphasize that improving immunity and inflammation to younger levels is only part of the goal. Such approaches also increase an individual's resiliency to withstand the sickness itself, since the whole body must respond to a major stressor like a coronavirus infection. By addressing the underlying biology of aging, geroscience aims to make the entire body more resilient, not just the immune system.
What Can We Do Today?
Older people are at such risk in part because the vigor of our immune response declines as we age. In addition, many are weakened by coexisting age-related conditions — such as heart disease, diabetes, and lung disease — that diminish resilience further. So, until a vaccine or effective treatment becomes available, how do we defend ourselves from infection beyond physical distancing and careful hand washing?
The authors recommend focusing on behaviors known to improve immune responses at any age:
- Eating well — a nutritious diet supports immune function and reduces inflammation
- Exercising as regularly as possible — even at home, and even in increasingly confined long-term care facilities
- Managing stress — chronic stress suppresses immune responses
- Getting enough sleep — sleep is critical for immune defense
Public health interventions that ensure access to healthy foods and safe environments are also critical, particularly for vulnerable populations.
Geroprotectors: Existing Drugs That Target Aging
In addition to a healthy lifestyle, the authors propose exploring interventions with existing drugs that have established safety profiles and target the biology of aging, immune mechanisms, and resiliency. These are called "geroprotectors" or "gerotherapeutics."
While many geroprotectors have been successfully tested in pre-clinical (animal) settings, to date none has been approved as a geroprotector for use in humans. Consequently, the authors strongly discourage self-medication with any of these compounds. These are experimental approaches that require proper clinical trials and medical supervision.
Metformin: A Promising Candidate
One of the most promising geroprotectors is metformin, a drug already used by more than 100 million people worldwide as a first-line treatment for type 2 diabetes. Metformin has been shown to target multiple hallmarks of aging and to increase health span and life span in animals. Observational and clinical trials in humans show that metformin use is associated with lower rates of:
- Type 2 diabetes mellitus (T2DM)
- Cardiovascular disease
- Cancer
- Cognitive decline
- Overall mortality
Interestingly, research dating back to the 1940s pointed to metformin and metformin-like biguanide drugs as preventing influenza and increasing immune response in humans, both in living subjects (in vivo) and in laboratory tests (in vitro). Metformin has 60 years of clinical experience, an exceptional safety record, and is generic and very cheap — just a little more than $0.10 per day.
Metformin has already shown protective capacity against COVID-19. In a retrospective analysis of 283 patients with type 2 diabetes from Wuhan, China, with confirmed COVID-19, investigators found no difference in the length of hospital stay. However, persons taking metformin had significantly lower in-hospital mortality: 3 of 104 patients (2.9%) compared with those not taking metformin, where 22 of 179 patients (12.3%) died. That is a dramatic difference.
Moreover, it was reported that diabetic women taking metformin had approximately a 20% decrease in mortality and approximately an 80% decrease in the inflammatory marker TNFα, a key molecule driving harmful inflammation.
mTOR Inhibitors: Rapamycin and Everolimus
A second line of drugs are mTOR inhibitors, which have been shown to increase health span and life span in almost all animals tested, from yeast to rodents. The mTOR inhibitor rapamycin reverses age-related declines in influenza vaccine response in mice.
Two Phase 2 clinical trials completed by resTORbio Inc. showed that the rapamycin derivative everolimus could enhance influenza vaccine response in healthy elderly people. The second Phase 2 trial also reported something striking: those treated with mTOR inhibitors for just 6 weeks had significantly fewer respiratory tract infections over the following year compared to those who received a placebo.
This suggests that short-term inhibition of mTOR may confer protection not only against the flu, but also against other common viruses — including other coronaviruses.
The Need to Advance Gerotherapeutics Now
Given the current public health crisis disproportionately affecting our aging population, the authors argue it is imperative to start discussing pragmatic approaches to rapidly test these drugs in the face of the COVID-19 pandemic.
At this stage, broad clinical trials of potential geroprotective therapies are needed to enable extensive data collection and analysis of their potential benefits and indications.
The potential public health impact is enormous. Metformin is broadly available, low-cost, and already taken chronically by more than 100 million people around the world. The authors note that even if only a small percentage of older people avoid hospitalization and death from COVID-19, the absolute benefits would be substantial.
Rapamycin has also been used clinically for many years with a well-established dosing and safety profile. While significant side effects are associated with high doses in patients undergoing daily rapamycin treatment (for example, organ transplant recipients), there is accumulating evidence that lower-dose treatment with rapamycin or its derivatives has minimal side effects in healthy individuals and may substantially improve immune function.
Randomized, controlled clinical trials are needed to assess whether rapamycin, metformin, and other potential geroprotective drugs can:
- Boost response to an eventual COVID-19 vaccine in the elderly
- Protect against COVID-19 infection altogether
- Reduce the severity of disease in those who do become infected
Biotech and the Drug Pipeline
Ongoing basic research in geroscience will produce a "pipeline" of novel compounds being developed by biotechnology companies around the world. This may provide new insights into how we can modify the aging process and boost our immune response — perhaps even improving the performance of a COVID-19 vaccine whenever it becomes available.
The authors are optimistic that continued investment in aging biology will yield a steady stream of new geroprotective candidates that can be tested against a wide range of infections and age-related diseases.
A Geroscience Approach Would Benefit Not Only the Chronologically Old
Epidemiological data indicates that COVID-19 is particularly aggressive among older adults. However, even within that group, there is a large heterogeneity of response: some individuals suffer severe effects and death, while others recover with symptoms little different from younger patients. This variability is a major characteristic of older populations.
There is a need to identify those individuals, within an age cohort, who are physiologically younger or older than their chronological age. While some older adults are more robust than expected, others are more fragile. Those who are more fragile (physiologically older) are likely to benefit most from geroscience-based approaches to improve their health.
Importantly, significant heterogeneity has also been identified among younger individuals. People who are chronologically young but display an advanced physiological age — often due to multiple health conditions or accumulated damage — would also benefit from a geroscience approach. These high-risk groups include:
- People with multimorbidity (multiple chronic diseases) in addition to SARS-CoV-2 infection
- Those with previous events that leave lasting effects (sequelae), such as controlled HIV infection
- People who have undergone previous chemotherapy or radiation treatment
- The disabled
- People with obesity
- People living in poverty who cannot easily modify their interactions with the environment
Strategic Research Directions: Evaluation of Aging, Multimorbidity, and Frailty
Multimorbidities — having multiple chronic diseases at once — have proven to be the main risk factors for poor outcomes in COVID-19 patients. In older patients, multiple aging-related diseases are often affected by multiple risk factors, further increasing disability and mortality.
The authors call for an urgent need to develop analytical methodologies that would allow a diagnostic evaluation of how several coexisting diseases contribute to COVID-19 outcomes. This includes identifying unique or combined parameters (biomarkers) that can serve as risk factors for the severity of disease. The ability to weigh risks from multiple diseases and their combinations may have critical implications for healthcare and social policy, both during the current crisis and in planning for future emergencies.
Several factors may be crucial for outcomes in elderly patients, for better or worse:
- Drug medications, such as ACE inhibitors (commonly used for blood pressure and heart failure)
- Vaccinations (including influenza and pneumococcal vaccines)
- Vitamins and other supplements
- Other interventions more prevalent in and differentially affecting older persons
The effectiveness of specific therapeutic regimens — such as different modes of oxygen delivery, resuscitation protocols, drugs, vaccines, and vaccine adjuvants — needs to be evaluated and adjusted specifically for older patients, whose management may differ dramatically from younger patients with critical illness.
This multimorbidity evaluation should be combined with a systematic assessment of aging and frailty status using standardized methods and measures. The authors call for strategies to conduct periodic frailty assessment with continuous, long-term follow-up of older persons. This could reveal not only global determinants of aging that are conserved across populations, but also local differences in aging and health around the world.
They also emphasize the need to develop standardized biomarkers of biological and physiological age — both to assess and predict risks of age-related ill health and to evaluate the effectiveness of potential geroscience therapies.
Finally, the authors advocate for involving the wider public in these evaluation studies — not just as test subjects, but as active and empowered "citizen-scientists." Increasing public science education in geroscience can help people evaluate evidence and participate meaningfully in research.
For such methodologies to work, it is essential to improve access, openness, sharing, and interoperability of clinical data on large groups of people — preferably long-term (longitudinal) data — including clinical conditions and diseases, demographic characteristics, and a wide range of evaluation parameters: biochemical, metabolic, immunological, physiological, and functional. Most of these data are already routinely available in clinical practice and research settings.
Policy Implications: Lessons From the Pandemic
The COVID-19 global emergency has emphasized to vast numbers of people the vital need to prevent old-age multimorbidity, protect the elderly, and improve their health span. Geroscience proponents have argued for the importance of such preventive measures for many years. Now we are witnessing in real time the disastrous consequences of the lack of such measures.
The authors argue that one of the most important lessons from this pandemic is the need to therapeutically address degenerative aging processes to prevent aging-related ill health as a whole. This understanding should translate into public health and research policies supportive of geroscience — improving funding, incentives, education, and institutional support for the field.
Conquering the current pandemic requires a multipronged approach:
- The "offensive" approach: developing vaccines and treatments specific to COVID-19
- The "defensive" approach: strengthening the resilience of affected individuals, regardless of the specific pathogen
The offensive part is unfortunately both slow and specific to the current virus or pathogen. In contrast, the defensive approach is pathogen-blind — the interventions work regardless of the infectious agent. A geroscience-focused response deployed now will remain relevant for future infections, whether pandemic, epidemic, endemic, or even individual infections affecting any one person.
What This Means for Patients
This editorial has several practical takeaways for patients and their families:
- Do not self-medicate. None of the drugs discussed in this article (metformin, rapamycin, everolimus) has been approved as a geroprotector for human use. The authors explicitly discourage self-medication with any of these compounds. Taking prescription drugs without medical supervision can be dangerous.
- Focus on proven lifestyle measures. Eating well, exercising regularly (even at home), managing stress, and getting enough sleep are behaviors that help improve immune responses at any age. These are safe, effective, and available to everyone.
- If you take metformin for type 2 diabetes, this research is reassuring. The data from Wuhan suggests that metformin use was associated with significantly lower mortality in diabetic COVID-19 patients (2.9% vs. 12.3%). Patients with diabetes should continue their prescribed medications and discuss any questions with their doctor.
- Evidence about other medications is still being gathered. For example, the question of whether ACE inhibitors (blood pressure medications) help or harm COVID-19 outcomes is still under investigation. Do not stop or change prescribed medications without consulting your healthcare provider.
- Frailty matters more than the number of candles on the cake. Age is a risk factor, but so are multiple chronic conditions. Individuals with multimorbidity — even those who are chronologically younger — need extra protection and attention during the pandemic.
- Clinical trials are how we will learn more. The authors urge rapid implementation of randomized, controlled trials of metformin, rapamycin, and other geroprotective drugs. Patients who are interested in participating in such research should discuss opportunities with their doctors.
In short, this research points toward a future where we treat aging itself as a modifiable condition — and in doing so, build a defense against infectious disease that works no matter what virus comes next.
Frequently Asked Questions
Which existing drugs might help protect against COVID-19?
Two types of drugs are discussed: metformin, used for type 2 diabetes, and mTOR inhibitors like rapamycin and everolimus. These target aging processes and may improve immune response. However, they are experimental for this purpose, not approved as geroprotectors, and should not be self-medicated.
How can older adults improve their immune response during the pandemic?
The authors recommend focusing on behaviors known to improve immune responses at any age: eating a nutritious diet, exercising regularly even at home, managing stress, and getting enough sleep. Public health measures ensuring access to healthy foods and safe environments are also critical.
Is it safe to self-medicate with metformin or rapamycin?
No. The authors explicitly discourage self-medication with any of these compounds because none has been approved as a geroprotector for human use. They are experimental approaches that require proper clinical trials and medical supervision. Taking prescription drugs without supervision can be dangerous.
Why are older adults more vulnerable to COVID-19?
Aging causes immunosenescence, a weakening of the immune system, and inflammaging, a state of chronic low-grade inflammation. Many older adults also have coexisting conditions like heart disease, diabetes, and lung disease that reduce resilience. As of April 2020, 77% of US COVID-19 deaths were people aged 65 and older.
What does 'treat aging itself' mean for future pandemics?
A geroscience approach targeting the aging process is pathogen-blind, meaning it could protect against not only COVID-19 but also future infections, epidemics, and pandemics. By strengthening the whole body's resilience, it aims to reduce the severity of disease regardless of the specific virus.
Should I seek a second opinion before taking metformin or rapamycin to protect against COVID-19 or future pandemics?
Before using metformin, rapamycin, or everolimus for anti-aging or immune resilience during COVID-19, a second opinion is advisable. These drugs are not approved as geroprotectors, and self-medication is explicitly discouraged. A specialist can help evaluate whether you are a candidate for any ongoing clinical trial and weigh potential risks versus benefits, especially if you have multiple chronic conditions or frailty. For type 2 diabetes patients, metformin has been associated with lower COVID-19 mortality, but do not change prescribed medication without medical advice. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original Article Title: Geroscience in the Age of COVID-19
Authors: Nir Barzilai, James C. Appleby, Steven N. Austad, Ana Maria Cuervo, Matt Kaeberlein, Christian Gonzalez-Billault, Stephanie Lederman, Ilia Stambler, and Felipe Sierra
Journal: Aging and Disease, Volume 11, Number 4; pages 725-729, August 2020
DOI: http://dx.doi.org/10.14336/AD.2020.0629
Affiliations: Albert Einstein College of Medicine (USA), Gerontological Society of America (USA), University of Alabama at Birmingham (USA), University of Washington (USA), Geroscience Center for Brain Health and Metabolism GERO (Chile), Buck Institute for Research on Aging (USA), American Federation for Aging Research (USA), Vetek Association (Israel), and National Institute on Aging, NIH (USA)
This patient-friendly article is based on peer-reviewed research published in an open-access scientific journal. The original editorial reflects the expert opinions and analysis of the authors as of June 2020. Since that time, further research on COVID-19 and geroprotective therapies has continued to evolve.
