Alzheimer’s Disease and Dementia

Despite intensive research, no preventive strategies or therapeutic interventions have proven effective for AD dementia. This failure is in large part because AD pathology, including the development of irreversible neurological damage, occurs years before the manifestation of clinical symptoms and cognitive impairment. Therefore, efforts to prevent and countermand AD dementia rely on early detection of presymptomatic pathological changes. A central goal of our research is to identify antecedent biomarkers and risk factors that predict later life AD vulnerability or resilience. We are examining the transitions from normal aging to mild cognitive impairment (MCI) and from MCI to AD and related disorders. In 2004, Swerdlow and Khan promulgated the “mitochondrial cascade hypothesis” for the development of sporadic late-onset AD, proposing that mitochondrial dysfunction is the primary event leading to the deposition of senile plaques and neurofibrillary tangles that are hallmarks of this disease.  An impressive body of work now highlights the central role of mitochondria in AD pathophysiology. Notably, multiple lines of evidence indicate that peripheral mitochondrial dysfunction accompanies changes in brain mitochondria in AD. Based upon this recognition, our team is utilizing peripheral cells to examine mitochondrial bioenergetics in older adults with varying degrees of AD risk and pathology. Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial function that is amenable to longitudinal human studies. Using this approach, we are identifying multi-parameter bioenergetic signatures that are associated with presymptomatic stages of AD and are predictive of AD progression.    

 

Aging and Physical Function

A central goal of our research is to understand the mechanisms underlying the decline of physical function with advancing age and age-related conditions, such as heart failure and obesity.  Moreover, we are testing interventions administered in both clinical and outpatient settings that are designed to improve physical ability.

-We are currently examining the role of mitochondrial bioenergetics in the physical function of older adults hospitalized for acute decompensated heart failure, the success of rehabilitation, and prognosis following hospitalization.  

-We are testing the hypothesis that bioenergetic decline, due to alterations in mitochondrial quality control, is a major contributor to exercise intolerance in older adults with stable chronic heart failure.  We are also working with collaborators to test optimized diet and exercise based intervention strategies designed to improve the exercise capacity of these patients.

 

Biomarkers of Human Aging

Several promising interventions have been demonstrated to promote longevity and healthspan in animal models. However, parallel human studies remain unfeasible based on the 40+ years of investigation likely required to complete such studies. Therefore, the National Institute on Aging has prioritized efforts to develop reliable biomarkers of human biological age. Multiple lines of evidence from our group and others indicate that the bioenergetic profiles of blood cells are related to multiple age-related diseases and disorders. Based on these findings, we have embarked on a new collaboration to test the hypothesis that peripheral blood cells exhibit epigenetic, transcriptomic, as well as bioenergetic changes related to fundamental mechanisms of human aging.

Circulating factors mediating systematic age-related bioenergetic decline

Blood-borne factors play a central role in aging. Using parabiosis, researchers have demonstrated that connecting the circulatory systems of young and old animals has systemic “rejuvenating” effects for the older animal. Conversely, our preliminary data demonstrate that factors present in the blood of older animals mediate age-related bioenergetic decline. By utilizing a heterochronic parabiosis mouse model, we observe that the bioenergetic capacity of skeletal muscle in young parabionts is severely diminished and quantitatively similar to parallel measures performed in the older parabionts as well as isochronic (old/old) controls. Various classes of circulating factors, including peptides, lipid metabolites, RNAs, and cytokines are being investigated for their roles in aging and various age-related diseases/disorders. However, it is unlikely that any single factor can be wholly responsible for the systemic effects of blood. To address this complexity, we are developing a novel systematic approach for studying human serum, and its components, in-vitro to identify circulating factor/s responsible for mediating changes in systemic bioenergetic capacity.

 

Current Funding Support:

R01 AG054523:  Blood Based Bioenergetic Profiling: A Novel Approach for Identifying Alzheimer's Disease Risk and Pathology (Molina PI)

R56 AG057864:  Circulating factors mediating systemic bioenergetic capacity in the pathogenesis and treatment of Alzheimer's Disease (Molina PI)

R01AG061805:  Exosome Mediated Alterations in Cellular Metabolism in the Pathogenesis and Progression of Alzheimer's Disease (Molina co-PI)

U01 AG060897:  Aging Biomarkers: Integrating Omic Profiles with Mechanistic Measures (Molina co-PI)

R21 AG051077:  The role of mitochondrial bioenergetics in post hospitalization syndrome and the rehabilitation of older patients after acute heart failure (Molina PI)