Geroscience: Frontiers in the Biology of Aging

Can we discover and understand the basic biological mechanisms and pathways that regulate the aging process? Moreover, by fundamentally understanding how and why processes of aging occur, can we devise the tools and technologies that will allow us to intervene, modulate, or perhaps reverse the full range of age-related diseases and disabilities that occur as consequence of the biology of aging?

This is the field of geroscience, and UPMC and the University of Pittsburgh are investing heavily in the pursuit of answers that will unlock the mysteries and complex processes of how and why human beings age, and ultimately how we can intervene to more effectively improve and extend one’s quality of life for as long as possible.

Helping to lead these emerging efforts in geroscience is Toren Finkel, MD, PhD, director of the Aging Institute, professor of medicine in the Division of Cardiology, and the G. Nicholas Beckwith III and Dorothy B. Beckwith chair in translational medicine. Dr. Finkel arrived at the University of Pittsburgh and UPMC in June 2017 aftera distinguished 25-year career with the National Institutes of Health, where he was the chief of the Center for Molecular Medicine in the National Heart, Lung, and Blood Institute (NHLBI) immediately preceding his arrival in Pittsburgh.

“The support and commitment from both the University of Pittsburgh and UPMC to grow into one of the premier basic biology of aging and translational research centers in the world was what really attracted me to come to Pittsburgh — to pursue my own research in the biology of aging front but also to help lead this effort with so many dedicated faculty across many disciplines,” says Dr. Finkel.

Understanding and Modifying the Basic Biology and Pathways of Aging

We know much about the basic biology of aging and its pathways, but significant gaps remain to be explored and understood. At the molecular level, it is known that accumulated nuclear DNA damage, shortening of the telomeres, problems with mitochondria, protein aggregation issues, and a host of quality control mechanisms can go awry as individuals’ age. Yes, there are multiple aspects or hallmarks of aging, and it’s certainly complex, “But that is not to say these processes are not regulated or cannot in some sense be malleable to interventions on the cellular or molecular level. We know, for example, in simple organisms that modifications to certain genes or proteins can have profound effects on both lifespan and health span. Similar modifications are what we hope to accomplish with human aging and age-related conditions such as Alzheimer’s disease,” says Dr. Frankel.

Fundamentally, Dr. Finkel and the groups working on these problems believe that once we more fully understand the basic mechanisms that drive aging, we will be in a position to develop new drugs that can regulate those mechanistic processes, leading to effective treatments for a wide range of age-related diseases. These studies will “lead to new approaches and new classes of medicines that we think will improve the quality of people’s lives,” says Dr. Finkel.

“We are not necessarily looking for or hoping to develop disease-specific therapies per se. We are interested in the molecules and processes that underlie the biology of aging, which, if we can intervene in, we think will prevent these sorts of illnesses from happening in the first place.”
-Toren Finkel, MD, PhD

A Translational Approach to Modifying Aging Processes Driving Disease

Cardiovascular disease, cancer, neurodegenerative diseases — these all have a powerful age-related component. Until now, most of the strategies for treating these broad categories of illness have been very disease-specific with some successes and equivalent number of failures. The approach that Dr. Finkel and colleagues are taking — the geroscience approach — means that, “We are not necessarily looking for or hoping to develop disease-specific therapies per se. We are interested in the molecules and processes that underlie the biology of aging, which, if we can intervene in, we think will prevent these sorts of illnesses from happening in the first place,” says Dr. Finkel. The Aging Institute, which Dr. Finkel now leads, has begun to expand its research focus and capabilities to pursue many avenues of basic and translational research with respect to the goals of geroscience writ large.

“In the end, we will have approximately 15 different laboratories all working on various aspects of aging biology, so the work here will be incredibly diverse. Coupled with the basic science labs will be a high throughput screening facility that will help significantly in our mission to develop entirely new classes of anti-aging drugs. We also hope to repurpose existing FDA-approved compounds that we think might be beneficial or applicable in modifying processes of aging,” says Dr. Finkel.

In the domain of basic science research, the laboratories of the Aging Institute are looking at such things as the connections between autophagy and mitophagy and their roles in removing or eliminating damaged proteins or organelles from the body and how this may contribute to aging itself. Other aspects of research will be focused on DNA damage repair, protein folding processes, mitochondrial and telomere research, and inflammation and its role in aging processes, among others.

For the testing of FDA-approved compounds, several projects are already in the planning phases, and the efforts from a broad peRspective will be spearheaded by Anne B. Newman, MD, and Daniel Forman, MD.

“Dr. Newman recently joined the Aging Institute as our clinical director, and she, along with Dr. Forman, who specializes in geriatric cardiology, will be leading many of our efforts to try and repurpose FDA-approved molecules for new, anti-aging uses,” says Dr. Finkel.

The diabetes drug Metformin will be analyzed in an internally led study in the setting of elective surgery with older adults.

“The goal is to see if metformin taken prior to surgery provides benefits, including improved survival or reduced hospitalization time. There is also a large, multicenter, NIH-proposed study of metformin in aging in which we also will be part of here at Pitt.”

Other areas of focus will likely look at reducing the nonspecific inflammatory responses seen in older adults.

“If you look at markers of inflammation, for example circulating interleukin-6 levels, it’s probably one of the best predictors of who is or is not going to live as they become elderly. It’s a marker of frailty and a sign of bad things to come. We are very interested in knowing whether biological agents that have been developed for other inflammatory conditions like rheumatoid arthritis or Crohn’s disease can be repurposed in a safe and effective way in older adults. Our hope is to negate or modify frailty and the propensity for disease that this nonspecific inflammatory response belies.”

The Emerging Paradigm of the Health Span

While a long life is generally desirable by most individuals, what is an extended length without commensurate quality? Much discussion is now focused on the idea of the health span — the length of time that one remains disease free and able to sustain a sufficient quality of life.

There is this observation that people who have incredibly long lives generally are relatively free from various morbidities. This theory, called the compression of morbidity, says that if as you extend life, you can also shrink the period of time an individual is suffering from morbidities.

“This is sort of the Holy Grail — to extend a person’s life span but compress the time period where they are incapacitated or debilitated. We think that it has to do with what’s driving the aging process, and again we are very optimistic about this approach and the research contributing to it. This is a new way of thinking about diseases, not in a disease-specific context but one whereby you modify aging itself,” says Dr. Finkel.