Building on two decades of research, investigators at University of Texas (UT) Southwestern have determined that “cellular housekeeping” can extend the lifespan and health span of mammals.
A study jointly led by Drs. Salwa Sebti and Álvaro Fernández, postdoctoral researchers in the Centre for Autophagy Research, found that mice with persistently increased levels of autophagy – the process a cell uses to dispose of unwanted or toxic substances that can harm cellular health – live longer and are healthier.
“Specifically, they have about a 10 per cent extension in lifespan and are less likely to develop age-related spontaneous cancers and age-related pathological changes in the heart and the kidney,” said Dr. Beth Levine, Director of the Centre for Autophagy Research at UT Southwestern.
Twenty years ago, Dr. Levine and her colleagues discovered beclin 1- a key gene in the biological process of autophagy. The group’s research has since shown that autophagy is important in many aspects of human health, such as preventing neurodegenerative diseases, combating cancer, and fighting infection.
In 2003, Dr. Levine’s team found that the genetic machinery required for autophagy was essential for the lifespan extension observed in long-lived mutant roundworms.
“Since then, it has become overwhelmingly clear that autophagy is an important mechanism necessary for the extended lifespan that is observed when model organisms are treated with certain drugs or when they have mutations in certain signalling pathways. The body’s natural ability to perform autophagy declines with aging, which likely contributes to the aging process itself,” said Dr. Levine.
Yet a crucial question remained unanswered: Is increased autophagy throughout mammalian life safe and beneficial? In other words, can autophagy extend lifespan and improve health span?
To answer this question, Dr. Levine and her UTSW colleagues created a genetically engineered mouse that had persistently increased levels of autophagy. The researchers made a mutation in the autophagy protein Beclin 1 that decreases its binding to another protein, Bcl-2, which normally inhibits Beclin 1’s function in autophagy. As the researchers expected, these mice had higher levels of autophagy from birth in all of their organs.
Last summer, Dr. Congcong He, a former trainee in Dr. Levine’s laboratory at UT Southwestern who originally made the mice, reported in PLOS Genetics that these mice are partially protected against mouse models of Alzheimer’s-like disease. The most recent findings now show that mice with increased cellular housekeeping live longer, healthier lives.
Additionally, in collaboration with Dr. Ming Chang Hu, Associate Professor of Internal Medicine and Dr. Orson Moe, Professor of Internal Medicine and Physiology, Nature study also shows that the mice with increased autophagy are protected from the early death that occurs when the anti-aging hormone klotho is lacking.