A targeted cellular cleanup process plays an important role not only in the breakdown of old or dysfunctional proteins but also in the regulation of metabolism, and its decrease appears to play roles in aging and age-related disease, said Ana Maria Cuervo during the Esther and Isadore Kesten Memorial Lecture on December 5.
Proteostasis, or maintaining a healthy balance of proteins, is critical for cell function and health, and part of maintaining that balance is the breakdown and recycling of old or damaged proteins, or autophagy. Cuervo, Distinguished Professor and Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases at the Albert Einstein College of Medicine and co-director of the Einstein Institute for Aging Research, is one of the world’s leading researchers in the field of autophagy, said Dean Pinchas Cohen in his introduction.
The loss of proteostasis, including a marked decrease in autophagy, is a hallmark of aging, Cuervo said. During the presentation, she shared her lab’s work on chaperone-mediated autophagy (CMA), in which specific proteins are targeted for destruction by molecules that “chaperone” the proteins directly into a cell’s lysosomes, organelles that contain digestive enzymes. The targeted cleanup process not only removes old or damaged proteins but also targets certain proteins to influence metabolism, she explained.
The Cuervo lab has demonstrated that CMA decreases with age, she said, and its decline has far-reaching consequences. Lower CMA activity is associated with degeneration in neural and muscle tissue, metabolic deficiencies, stem cell dysfunction, immune system aging, deregulation of circadian rhythm, development of malignancy, and more, Cuervo said.
“CMA activity is compromised in multiple human disorders, from neurodegenerative conditions, immune disorders, metabolic and cardiovascular conditions, cancer, and eye diseases,” she noted.
Cuervo and her team are investigating the molecular mechanisms behind why CMA decreases with age. About 20 genes and the proteins they code for appear to be responsible for regulating the process; one such protein is lysosome-associated membrane protein type 2A, or LAMP-2A. LAMP-2A resides on the surface of lysosomes and acts as a receptor for the molecular chaperone, but the number of these receptor sites decreases with age, Cuervo explained.
The Cuervo lab has developed mouse models with inactivated LAMP-2A to study how blocking CMA affects health and aging. Her team also developed a mouse model that could have a gene activated later in life to produce more LAMP-2A. When LAMP-2A dramatically decreases at mid-life, the treated mice made to keep expressing “younger” levels of LAMP-2A showed preserved CMA function, and compared to untreated mice, the treated mice had longer, healthier lifespans with less frailty and better functional outcomes.
“This gave us a proof-of-concept that preserving CMA activity later in life might be beneficial,” Cuervo said.
Cuervo and her team next wanted to investigate whether treatment with other chemical compounds could promote CMA activity. Giving mice a novel drug that modulates an inhibitor of CMA successfully increased CMA activity, Cuervo said; in mice genetically engineered to develop frontotemporal dementia, drug treatment improved short-term memory and reduced the disease’s telltale tau pathology in the brain. In another experiment, late middle age healthy mice that received the drug showed fewer signs of aging, including better motor coordination, fewer senescent cells, better immune response, and higher stem cell activation.
“By acting on CMA, we are acting on the different hallmarks of aging,” Cuervo said. “We think that CMA might be a good gerotherapeutic target.”
The Esther and Isadore Kesten Memorial Lecture was established in 1973 by Alan Davis, son of Sophie and Leonard Davis, in memory of his grandparents. The funds from this endowed lectureship allow the USC Leonard Davis School to annually honor individuals whose research in gerontology has contributed significantly to the understanding of the aging process.
