A Research Agenda to Slow Aging and Slow Disease
Scientists who study aging now generally agree that it is malleable and capable of being slowed. Rapid progress in recent years toward understanding and making use of this malleability has paved the way for breakthroughs and interventions that will increase human health in later life by opposing the primary risk factor for virtually every disease we face as we grow older—aging itself. Better understanding of this “common denominator” of disease could usher in a new era of preventive medicine, enabling interventions that stave off everything from dementia to cancer to osteoporosis. Poised as we are for an unprecedented aging of our population and staggering increases in chronic age-related diseases and disabilities, even modest extensions of healthy lifespan could produce outsized returns of extended productivity, reduced caregiver burdens, lessened Medicare spending, and more effective healthcare in future years. The field of aging research is poised to make transformational gains in the near future. Few, if any, areas for investing research dollars offer greater potential returns for public health.
While there has been great excitement surrounding the progress in aging research, a large gap remains between promising basic research and healthcare applications, and closing that gap will require considerable focus and investment. The field would benefit greatly from coordinated efforts within the National Institutes of Health to improve the quality and pace of research that advances the understanding of aging, its impact on age-related diseases, and the development of interventions to extend human healthspan. In addition to the National Institute on Aging (NIA), the coordinating committee would be most effective if it also included the National Human Genome Research Institute and representatives from the many major-disease focused institutes that have some role in aging research. An even broader interagency committee composed of various agencies within the Department of Health and Human Services could further speed the process of turning this research into healthcare advances.
An increase in funding for aging research is also urgently needed to enable scientists to capitalize on the field’s recent exciting discoveries. Congressional appropriations to fund the efforts that grow out of the coordinated efforts of the NIH would allow for major advances across diseases. Advocates for age-related diseases like Alzheimer’s disease and cancer have called for Congressional appropriations of $2 billion annually in order to achieve major breakthroughs in treating and curing those diseases. Thus, a similar goal for aging research on the basic underpinnings of aging over the next 3 to 10 years seems modest considering its great potential to lower overall disease risk (including Alzheimer’s, cancer, and more) and add healthy years to life.
The payoffs from such focused attention and investment would be large and lasting. Therapies that delay aging would lessen our healthcare system’s dependence on the relatively inefficient strategy of trying to redress diseases of aging one at a time, often after it is too late for meaningful benefit. They would also address the fact that while advances in lowering mortality from heart attack and stroke have dramatically increased life expectancy, they have left us vulnerable to other age-related diseases and disorders that develop in parallel, such as Alzheimer’s disease, diabetes, and frailty. Properly focused and funded research could benefit millions of people by adding active, healthy, and productive years to life. Furthermore, the research will provide insights into the causes of and strategies for reducing the periods of disability that generally occur at the end of life. As University of Michigan gerontologist Richard Miller aptly puts it, “The goal isn’t to prolong the survival of someone who is old and sick, but to postpone the period of being old and sick. Not to produce a lot more standard-issue 100-year-olds, but to produce a brand new kind of 100-year-old person.”
Key research questions within four categories—cell replacement, inflammation, stress response, and tools & models—are outlined in this Research Agenda.* They were chosen by a team of leading U.S. and European scientists with the goal of identifying some of the most promising research in the field. To-date they have been endorsed by more than 65 leaders in the field. The agenda is not intended to be exhaustive,
*Please note that in addition to the broad research questions below, the team of scientists broke out these questions even further and the details are available in the unabridged version of the research agenda.
One hallmark of aging tissues is their reduced ability to regenerate and repair. Many tissues are replenished by stem cells. In some aged tissues, stem cell numbers drop. In others, the number of stem cells changes very little—but they malfunction. Little is currently known about these stem cell declines, but one suspected cause is the accumulation of “senescent” cells. Cellular senescence stops damaged or distressed cells from dividing, which protects against cancer. At advanced ages, however, the accumulation of senescent cells may limit regeneration and repair, a phenomenon that has raised many questions. Do senescent cells, for instance, alter tissue “microenvironments,” such that the tissue loses its regenerative powers or paradoxically fuel the lethal proliferation of cancer cells?
A robust research initiative on these issues promises to illuminate the roots of a broad range of diseases and disabling conditions, such as osteoporosis, the loss of lean muscle mass with age, and the age-related degeneration of joints and spinal discs. The research is also essential for the development of stem cell therapies, the promise of which has generated much public excitement in recent years. This is because implanting stem cells to renew damaged tissues in older patients may not succeed without a better understanding of why such cells lose vitality with age. Importantly, research in this area would also help determine whether interventions that enhance cellular proliferative powers would pose an unacceptable cancer risk.
Acute inflammation is necessary for protection from invading pathogens or foreign bodies and the healing of wounds, but as we age many of us experience chronic, low-level inflammation. Such insidious inflammation is thought to be a major driver of fatal diseases of aging, including cancer, heart disease, and Alzheimer’s disease, as well as of osteoporosis, loss of lean muscle mass after middle age, anemia in the elderly, and cognitive decline after 70. Indeed, just about everything that goes wrong with our bodies as we age appears to have an important inflammatory component, and low-level inflammation may well be a significant contributor to the overall aging process itself. As the underlying mechanisms of age-related inflammation are better understood, researchers should be able to identify interventions that can safely curtail its deleterious effects beginning in mid-life—broadly enhancing later-life—and with negligible risk of side effects.
A central theme in modern aging research—perhaps its “key” discovery—is that the mutations, diets, and drugs that extend lifespan in laboratory animals by slowing aging often increase the resistance of cells, and animals, to toxic agents and other forms of stress. These discoveries have two main implications, each of which is likely to lead to major advances in anti-aging science in the near future.
First is the suggestion that stress resistance may itself be the cause (rather than merely the companion) of the exceptional lifespan in these animal models, hinting that studies of agents that modulate resistance to stress could be a potent source of valuable clinical leverage and preventive medicines. Second is the observation that the mutations that slow aging augment resistance to multiple varieties of stress—not just oxidation, or radiation damage, or heavy metal toxins, but rather resistance to all of these at the same time.
The implication is that cells have “master switches,” which like rheostats that can brighten or dim all lights in a room, can tweak a wide range of protective intracellular circuits to tune the rate of aging differently in long-lived versus short-lived individuals and species. If this is correct, research aimed at identifying these master switches, and fine-tuning them in ways that slow aging without unwanted side-effects, could be the most effective way to postpone all of the unwanted aspects of aging through manipulation of the aging rate itself. Researchers have formulated, and are beginning to pursue, new strategies to test these concepts by analysis of invertebrates, cells lines, rodents, and humans, and by comparing animals of species that age more quickly or slowly.
Gerontologists’ toolboxes have been greatly expanded by the same advances that have brought us bioengineered medicines and genetic tests that help oncologists select the best drugs to deploy against certain cancers. Applying the tools to study aging remains a work in progress, however, due both to the costs of new technologies and to the inevitable learning curves for mastering and harnessing them. Meanwhile, new animal models are being developed, such as the incredibly durable naked mole-rat, which promise profound insights into the aging process and how it might be altered to increase healthy life.