Aging and Disease

People who have a healthy lifestyle and good medical care are likely to live about 80 years, often in good-to-excellent health. However, as people get older, their risks for many diseases (some of them potentially deadly) go up dramatically—doubling about every 8 years. Cancer, arthritis, serious problems with thinking and memory, death from flu or COVID-19, and heart attacks all increase with each decade of life, along with cataracts, hearing problems, skin wrinkles, and a long list of other age-related issues. It would be hard to find an 85-year-old person with none of these problems, but rare to find a 20-year-old with many of them.

Three kinds of scientific evidence show that aging and the diseases of aging are linked, and that it is not just a coincidence that all these problems happen to develop at roughly the same age. First, some breeds of dogs (usually small dogs) live a lot longer than dogs of other, larger breeds. Most diseases of aging occur later in small dogs than in larger ones. Therefore, it makes sense to say that aging runs more slowly in small dogs, delaying most aging-related problems and keeping these dogs alive and healthy for longer. This is also true for horses.

Second, data show that most of the age-related problems detected in 80-year-old people also happen in 2-year-old mice, 10–15-year-old dogs, 25-year-old horses, 40-year-old chimpanzees, and 60-year-old albatrosses and elephants. In short, aging runs more slowly in long-lived species of animals [1].

Third, it has been known for about 90 years that reducing the amount of calories mice or rats eat by 30%-40% can extend their lifespan by about 30%-40% and postpone (delay) most age-related changes. These “calorie-restricted” lab animals have a delay in their risks of many forms of age-related illnesses, and that is why they live such a long time.

These ideas clearly imply that if researchers found a way to make aging run at a slower pace, people would stay healthier for longer and live longer than they do today.

Can We Slow Aging?

Since the mid-1990s, it has been clear that we can slow aging. In addition to the calorie restriction story, the next compelling evidence came from genetic studies. In the 1990s, several research groups reported that certain changes, called mutations, in specific genes could dramatically increase lifespan in a species of worms called C. elegans. Similarly, mutations that extend the lifespan of laboratory mice were first reported in 1996. Although changing human genes is not practical, these studies raised hopes that it might be possible to find medicines that can postpone aging and aging-related diseases.

The first organized approach to finding anti-aging drugs, called the Interventions Testing Program (ITP), began in 2003 [2]. The ITP tests about five drugs or natural products each year to see if they extend lifespan in mice. So far, 14 drugs have been shown to produce longer lifespans in male mice, female mice, or in both sexes. For seven of these drugs, the lifespan increase reached 10% or higher. This is quite a lot: if a similar percentage change could be achieved in people, it would extend healthy human lifespan about three times more than a pill that prevented all adult cancers, or all heart attacks.

The largest effect so far seen in the ITP studies was produced by a combination of two drugs, rapamycin plus acarbose [3, 4]. Male mice given both drugs lived 29% longer than untreated mice (Figure 1). Some of the mice treated with ITP drugs have also been evaluated for aspects of health that are relevant to human aging, such as strength, overall activity, balance, and brain and heart health, and they were found to resemble younger mice in these ways as well. These experiments give hope that it may be possible to find drugs that work in humans to postpone age-related illnesses by slowing the rate of aging, and thus to increase healthy human lifespan.

Testing Anti-Aging Pills—The Slow, Expensive Way and a Faster, Cheaper Way

The standard way to test a new drug to see if it can extend mouse lifespan is to give the drug to a few hundred mice and then see how long they live (Figure 2). But this takes about 4 years and costs several hundred thousand US dollars per experiment! If positive results are seen with a drug, then follow-up studies are needed to see which dose(s) might be best and to see if the drug also slows the loss of brain fitness, physical fitness, resistance to infection, and other aspects of good health. These follow-up experiments are also expensive and take many years to complete. Unfortunately, about 85% of initial lifespan experiments “fail”, in the sense that the drug being tested does not increase mouse lifespan. Is there a way to speed up this discovery process and make it less expensive?

Scientists are now exploring a faster way to search for anti-aging drugs. Instead of waiting years to see whether treated mice live longer, they are looking for changes in blood and other parts of the body that seem to appear again and again in mice whose aging has already been slowed by known anti-aging drugs, diets, or mutations. These changes are called aging rate indicators (ARIs) [5]. In this approach, researchers give mice a new drug for months rather than years, and then measure several ARIs and compare the results with patterns already seen in slow-aging mice (Figure 3). If a new drug changes several known ARIs in the same direction as known lifespan-extending treatments, that is a clue that the new drug may slow aging too. If ARIs prove reliable, they could help researchers test possible anti-aging drugs more quickly (and at a lower cost) in mice—and, eventually, in humans.

Although studies of ARIs are at an early stage, they have so far shown changes in fat, liver, muscle, brain, immune cells, and blood plasma that are shared by at least 10 kinds of slow-aging mice, including 4 varieties where the aging process was slowed by drug treatment. These drug-induced changes, as well as similar changes caused by a calorie-restricted diet, can be seen as early as 8 months after young adult mice begin treatment, rather than the 4 years needed to complete a lifespan experiment using the older, traditional method shown in Figure 1.

Scientists are now improving, challenging, and extending these initial findings. They want to know how quickly ARIs change, whether some change before others, and whether the same ARIs appear when anti-aging drugs are given to older mice. They also want to know how reliable ARIs are as clues to slower aging—for example, whether some drugs change ARIs without extending lifespan, or extend lifespan without changing the known ARIs. Perhaps most importantly, scientists are still trying to understand why such a wide range of ARIs appears when mice enter a slow-aging state, whether through genetic changes, diet, or drug treatment.

Moving to Human Anti-Aging Drugs

The hoped-for payoff from these experiments is to find drugs that slow aging in people, helping to delay many diseases and other problems that become common in old age. Since humans can live a long time, it may take 5–20 years to detect whether an anti-aging drug prolongs survival or slows serious health declines. Studies that last only a year or two are unlikely to detect a decline in aging rate even if the drug does have a major effect on aging and the study includes hundreds of volunteers. Can using the ARI approach speed up human anti-aging research?

Work on slow-aging mice has identified some ARIs that can be detected in blood plasma, and would therefore be testable in small blood samples taken from humans. These ARIs include small molecules like certain lipids (fats) and modified amino acids, and larger molecules such as specific proteins. Researchers want to know whether testing ARI levels in blood plasma of a group of healthy 60-year-olds, for example, could help identify which people are most likely to remain healthy over the next decade.

Some of the drugs that slow aging in mice are already being used to treat specific human diseases and thus could be safely given to volunteers. Once researchers identify a set of ARIs in human plasma that seems likely to predict the pace of aging-related changes in healthy middle-aged adults, these ARIs could be used to test possible anti-aging drugs in studies that will only require a few dozen participants and only last a year or so, rather than 10–20 years. In these new studies, researchers could ask whether the same substances in the blood that act as ARIs in mice also change in people who take a possible anti-aging medicine. If researchers test 20 possible drugs and find that one or two of them change these ARIs in a pattern similar to that seen in mice, those drugs could then be chosen for longer studies that look at health outcomes like physical fitness, memory, and disease risks, with a better chance of success.

Would It Be Ethical to Slow Aging?

Is it ethical (“the right thing to do”) to slow aging? Yes, it is. Just as it is ethical to prevent or treat cancer or heart attacks, or to protect people from COVID-19 or flu, it is also ethical to prevent the serious illnesses that affect people as they age. The reasoning is the same: this research can prevent harm, which is a good goal.

Some people disagree with this point of view, but we think their arguments are not convincing. Some people point out that very old people are often seriously ill and sometimes have dementia or other diseases that are painful for both the patient and their family. They argue that keeping these people alive longer, in great distress, might be unethical. So far, however, the evidence from mice tells us that effective anti-aging drugs postpone aging related conditions—they keep mice healthier for longer periods.

Other people worry that, if people live longer, the world will become overpopulated and the resources we need will be used up more quickly. However, this is already happening even without anti-aging medicines, so we must address these problems whether or not we discover anti-aging drugs that work in people. This will not be easy, and will probably require major adjustments in how rich and poor people (and nations) obtain food, housing, clean water, and medical care, including safe and effective drugs. Development of new drugs that slow aging, along with vaccines to prevent infections and medicines to protect people from diabetes and heart attacks, will not make it any harder to find solutions to these major environmental and political challenges.

In short, scientists do not yet know whether anti-aging drugs will work in people, but research in mice offers real reasons for hope and new directions for experimentation. By learning how to measure slower aging and test possible medicines more quickly, researchers may eventually find ways to help people stay healthier later in life.

Glossary

Lifespan: ↑ The length of time an organism lives, from birth to death.

Mutations: ↑ Changes in DNA, some of which can change how an organism grows, works, or survives. Some mutations do nothing, some cause problems, and a few can lead to better health or longer survival.

Aging Rate Indicators: ↑ Changes in blood or tissues that help scientists measure how quickly an animal or person is aging.

Blood Plasma: ↑ The liquid part of blood that contains proteins, nutrients, hormones, and other molecules that can reveal what is happening in the body.

Conflict of Interest

MK is CEO of Optispan, Inc.

The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

RAM acknowledges support from NIH grants no. AG024824, no. AG023122, and no. AG022303, and from the Glenn Foundation for Medical Research. SNA acknowledges support from NIH grants no. AG050886, no. AG057434, and no. AG072137 as well as a Protective Life Insurance endowment. MK received funding from Optispan, Inc. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

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