Exercise, Age-Related Memory Decline, And Hippocampal Function

In the US, increased length of life and reduced morbidity and mortality have resulted in a
growing number of older adults, the demographic "time bomb" often referred to in discussions
of public policy. According to the Census Bureau, the population aged 65 and over will double
in size within the next 25 years. Moreover, these older adults will live healthier lives than
their predecessors. While this increased length of a healthy life is an undeniable societal
benefit, it brings with it a major societal problem: an epidemic of aging-related cognitive
decline. The need to develop interventions to address this growing problem is urgent.
Aging-related cognitive dysfunction is not diffuse; rather it targets selected brain areas,
in particular the frontal lobes and the hippocampal formation. The separate but
interconnected subregions of the hippocampus are differentially vulnerable to pathogenic
mechanisms, including the normal aging process. A range of in vivo and post-mortem studies
have converged on the dentate gyrus (DG) as the hippocampal subregion differentially targeted
by the aging process. As with pathogenic processes, any intervention that improves brain
function does so with regional selectivity. One such intervention is physical exercise, which
has been shown to improve both frontal lobe and hippocampal function. Using a high-resolution
variant of functional magnetic resonance imaging (fMRI), the investigators have demonstrated
that aerobic training selectively benefitted DG function both humans and mice. In addition,
improvement in DG function was associated with improved performance on a word list learning
task but not in tasks conventionally thought to be frontal lobe dependent. The human part of
the study had significant shortcomings, however: it was small (N = 11), lacked a control
group, enrolled only young subjects (age 20-45 years), and employed only a limited
neuropsychological testing battery. The overall goal of this proposal is to use the
high-resolution variant of fMRI to test the hypothesis that aerobic training will induce
improvements in DG function in a sample of younger (age 20-35) and older (50-65) adults,
assigned randomly to an active training condition or wait list control group. The
investigators will use more comprehensive neuropsychological testing to examine the
relationship between changes in DG function and selected cognitive capacities. Taken together
with the observation that normal aging differentially targets the DG, this research program
will establish that physical exercise is an effective approach for ameliorating the insidious
cognitive slide that occurs in aging. Thus, the potential significance of this application is
substantial.

Inclusion Criteria:

1. Age 20-75 years

2. English-speaking

3. Ambulatory

4. "Average" fitness as determined by ACSM's Guidelines for Exercise Testing and
Prescription (for men, VO2max < 43 for age 20-39 years, < 38 for age 40-49 years, < 35
for age 50-59, < 31 for age 60-75; for women, < 36 for age < 30 years, < 34 for age
30-39 years, < 32 for age 40-49 years, <25 for age 50-59 years, < 24 for age 60-75
years

5. BMI <35

Exclusion Criteria:

1. Ischemic changes or abnormal resting cardiogram, abnormal blood pressure responses, or
an significant ectopy during aerobic capacity testing

2. Cardiovascular disease

3. BMI > 35

4. Uncontrolled high blood pressure (systolic blood pressure ≥ 140 mmHg; or diastolic
blood pressure ≥ 90mmHg on two measures)

5. Any condition for which aerobic training is counter-indicated, including persons with
evidence or history of medical or orthopedic conditions which might make participation
problematic.

6. Current or recent (evidence of disease x 5 years) non-skin neoplastic disease or
melanoma. Prostatic carcinoma will not be grounds for exclusion.

7. Active hepatic disease (not a history of hepatitis) or primary renal disease requiring
dialysis, primary untreated endocrine diseases, e.g., Cushing's disease or primary
hypothalamic failure or insulin dependent diabetes (Type I or II). Welltreated
hypothyroidism will not be excluded.

8. History of chemotherapy

9. HIV infection

10. Pregnant or lactating (participation allowed 3 months after ceasing lactation).

11. Medications that alter inflammation or autonomic nervous system activity

12. Any history of psychosis or ECT

13. Current or recent (past one year) Major Depressive Disorder, Bipolar Disorder

14. Current or recent (within past 12 months) alcohol or substance abuse or dependence.
Recent use (past month) of recreational drugs.

15. Dementia Rating Scale (DRS) score less than 135. Medical History Interview

16. Neurological Disorders Dementia Rating Scale

17. Stroke Telephone screen

18. Alzheimer's Disease Telephone screen

19. Smoking Telephone screen

20. Prior participation in another Dr. Sloan Exercise Study

21. MRI Exclusion Criteria: Cardiac Pacemaker; Internal Pump; Insulin Pump; Tattoo;
eyeliner; Wire Sutures; Internal Metal Objects; Metal Slivers in Eye; Prosthesis;
Hearing Aid Implants; Neurostimulator; Metal Fragments; Brain Aneurysm Clips; Vascular
Clips; Breast Expander; Vena Cava Filter; Heart Valve; Metal Stents; Asthma;
Hay-Fever; Sickle Cell Disease; Kidney Disease; Machinist or ever worked with heavy
metals Interview; Contraindication to gadolinium, including prior adverse reaction to
gadolinium, past or current history of severe breathing difficulty that has been
treated by a physician (e.g., asthma, COPD, etc.), and sickle cell disease. History of
renal impairment or estimated glomerular filtration rate <30 L/min/1.73m2 is also
exclusionary; Machinist or ever worked with heavy metals Interview; Have had more than
one MRI scans with Gadolinium