Heidi Pak, PhD

What inspired you to pursue aging research?

One day my grandmother asked a rhetorical question which has always stuck with me: “What is the point of living if I’m in pain all the time?” At the time, I didn’t think much of it; I thought it was just a traditional complaint of an elderly woman in the inevitable process of life. However, this question became apparent when I saw a progressive decline in my grandmother’s wellbeing. While she never had a history of life-threatening diseases, she struggled with arthritis and eventually sarcopenia making it extremely difficult for her to walk even for a simple task. Modern medicine has done an amazing job in extending the life of a person; however, this has not been paralleled with health. Therefore, our growing aging population is living with one form of debilitating diseases caused by aging for a significant portion of their life. My goal in pursuing aging research is to understand the molecular mechanism that drives aging to ultimately develop novel therapeutic methods to extend health and eliminate the debilitating aspect of aging.

In your view, what does AFAR mean to the field, and what does it mean for you to receive an AFAR grant now?

To me, AFAR represents the growing interest and the importance in understanding the biology of aging. AFAR plays a critical role in supporting early career scientists, such as myself, and I am honored to be selected as one of the postdoctoral fellows this year. With the AFAR grant, I now have the flexibility to pursue ambitious projects that I am passionate about and establish several projects for future grant applications. Lastly, with the prestigious support of AFAR, I hope to establish myself as an aging researcher in the aging field. I would like to sincerely thank the Glenn Foundation Fellowship Committee for giving me this opportunity.

What is exciting about your research’s potential impact?

Calorie restriction (CR) research has existed for over a century with various theories proposed over the years in how it mediates health and lifespan. During its long history, it has been postulated that CR works by protein restriction, decreased growth hormone signaling, calories alone, etc. More recently the self-imposed fasting behavior in laboratory animals, as well as time-of-day feeding, may be required to elicit the full benefit of a CR diet. In a laboratory setting, animals are fed in a very controlled manner, which means animals are fed exactly at the same time under the same condition every single day. Therefore, I thought that this habitual eating pattern (feeding entrainment) in CR mice, trains the metabolic processes to maintain a metabolic memory, which ultimately leads to efficient storage and utilization of fuel sources. But how do you uncover feeding entrainment mechanisms? This can be best done by observing for the phase shift kinetics as described by Ueli Schibler. Most CR studies are limited to analyses well after the transition from an ad libitum diet to CR, meaning we observe changes when the diet has been fully established. A limitation in this approach is that we do not know which metabolic pathways are first impacted from the diet, and how this affects other metabolic processes. Additionally, many of the changes are reported only at a single time-point which does not reflect the dynamic nature of our metabolism. Therefore, to determine the phase shift kinetics from ad libitum to a CR diet, we must capture the transition phase (beginning of the diet) and at multiple time points during a diurnal cycle. I am excited about the possibility that the proposed research may take CR research into a new direction. From this study, we may be able to uncover feeding entrainment mechanisms that drives the CR response, and perhaps reveal that a simple habitual eating pattern, instead of a strict calorie restricted or fasting diet, may extend health and longevity.

How would you describe your research to a non-scientist?

As the global population ages, developing interventions that can prevent or delay age-associated diseases is of increasing importance to promote healthy aging. Calorie restriction (CR), a reduction in caloric intake without malnutrition, is the most effective non-pharmacological intervention that extends both lifespan and healthspan in diverse species ranging from yeast to mice and non-human primates. However, an abstemious CR diet is notoriously difficult to maintain. Despite a century of study, the mechanism by which CR promotes health and longevity is still unknown. Understanding the physiological and molecular mechanisms by which CR promotes health may allow the development of dietary regimens or pharmaceuticals that can mimic the effects of CR without requiring reduced caloric intake.

A traditional calorie restricted (CR) regimen, where mice are fed once per day imposes a prolonged fasting period – animals consume their daily portion within ~2 hours and fast for ~22 hours. This is in sharp contrast to the normal food consumption pattern of a mouse, in which eating occurs in smaller bouts throughout the day, with 60-80% of calories consumed during the dark cycle. However, majority of the research in this field has focused on determining the changes that occur from restricting calories, and not from the feeding behavior of the model organism. Additionally, these studies are limited to analyses well after the transition from an ad libitum (AL) diet to CR, and to fully understand how this change happens, the transition phase must be captured. Therefore, the overall objective of the proposed project is to identifying key transcripts and metabolites that are altered during the transition phase from an ad libitumdiet to CR diet to determine feeding entrainment mechanisms. The proposed experiments will address long-standing biological questions regarding the mechanisms by which CR promotes metabolic health, fitness, and longevity, and will provided much needed insight into the role of feeding behavior in the mammalian response to CR.