This is part six of a series of blogs from attendees at ACSM's Conference on Integrative Physiology of Exercise. The following blog is a reflection on the session titled "How Exercise Promotes Brain Health in Aging" by session co-chair Dr. Jill Barnes. 

At ACSM’s Conference on Integrative Physiology of Exercise, a common theme was how regular exercise is beneficial for multiple organ systems, and how exercise may prevent or delay the onset of age-related diseases. The last session of this conference discussed how exercise may promote brain health and reviewed recent evidence from exercise-based randomized clinical trials (RCTs) in humans.

In the U.S., physical inactivity is the number 1 modifiable risk factor for Alzheimer’s disease (AD). Barnes & Yaffe calculated that 21 percent of AD cases in the U.S. could be attributable to physical inactivity and increasing the proportion of the U.S. population who are physically active by 25 percent may prevent more than 200,000 AD cases. As with many diseases, increasing physical activity could also have a substantial impact on the social and economic impacts of AD!

At this conference, Drs. Marcelo Wood and Carl Cotman, both from University of California-Irvine, reviewed studies in mice demonstrating hippocampal neurogenesis and enhanced learning and memory after access to a running wheel. These studies are quite convincing (see this recent review), and the work of Drs. Wood and Cotman seeks to understand the underlying mechanisms by which exercise enhances brain health. Dr. Wood discussed the role of histone deacetylase 3 (HDAC3) in inhibiting new memory formation in older mice and proposed the hypothesis that exercise stimulates epigenetic mechanisms that may include histone modifications. Dr. Cotman spoke about how increases in brain-derived neurotrophic factor (BDNF) with exercise may enhance the sensitivity of downstream signaling cascades to promote memory and learning. In addition, previous exercise training may “prime” the system so that BDNF levels are quickly restored with subsequent exercise, promoting neuronal adaptations.

Despite the evidence on the benefits of exercise on brain health, and specifically animal models demonstrating hippocampal neurogenesis, angiogenesis and enhanced cognitive function with exercise, the translation to aging humans is less convincing. In fact, recent systematic reviews state that the strength of the data showing that aerobic exercise increases hippocampal volume in humans is modest at best and that conclusions regarding exercise on the default mode network (an important brain network relevant to AD) could not be made. Additionally, a recent trial in individuals with dementia concluded that exercise training did not slow cognitive impairment.  

As an exercise physiologist, this is difficult to comprehend! Why is there a difference in effectiveness between animal studies and cross-sectional studies in humans vs. RCTs utilizing exercise interventions?

Next, Dr. Fang Yu from the  University of Minnesota and Dr. Jeffrey Burns from the University of Kansas Medical Center spoke on their recent work. Both investigators are at the forefront of this area with substantial expertise in conducting RCTs on exercise and brain health. They reviewed the evidence regarding frequency and duration of exercise and the relationship to risk of dementia. Many of the studies that do show a beneficial effect of exercise on hippocampal volume or memory also demonstrate a measurable change in fitness (such as VO₂ peak). So, for exercise to have a detectable effect on the brain, the dose should be high enough to improve fitness. It seems intuitive that a significant exercise dose is necessary for an effect on the brain, but we must consider that exercise-based RCTs, especially in adults with cognitive impairment, are difficult to conduct due to logistical and ethical issues.

This session highlighted the fascinating physiology underlying exercise-induced adaptations in the brain and brought up many unresolved questions in humans: 1) what is the appropriate dose of exercise for brain health? 2) how can adherence be enhanced in adults with cognitive impairment? and 3) what ways can exercise be optimized to increase the effectiveness of exercise? These questions require more research in humans. There are numerous ongoing clinical trials that will attempt to address these research questions and, hopefully, provide convincing evidence that regular exercise in humans plays an important role in the prevention of age-associated cognitive decline and AD.

Read part 1 of this series: "Can Exercise Fill the Reductionist Gap? Reflections on Dr. Michael Joyner's Keynote."
Read part 2 of this series: "Are Exercise 'Mimetics' a Realistic Substitute for Exercise Training? Reflections on the Debate." 
Read part 3 of this series: "Exercise and Energy Restriction to Improve Health: Recent Research." 
Read part 4 of this series: "Molecular Transducers of Physical Activity (MoTrPac) Update." 
Read part 5 of this series: "Metabolic Flexibility in Health & Disease: A Symposium Summary." 

Jill Barnes, Ph.D., FACSM, is an Assistant Professor at the University of Wisconsin-Madison in the Department of Kinesiology, and has an affiliate faculty appointment in the Division of Geriatrics and Gerontology in the School of Medicine and Public Health. She served as co-chair of the “How Exercise Promotes Brain Health in Aging” symposium at ACSM's Conference on Integrative Physiology of Exercise.