Cellular recycling process is key to longer, healthier life

May 30, 2018 by Deborah Wormser, UT Southwestern Medical Center
The UTSW research team that reported on autophagy in Nature includes, from left: (front) Drs. Ming Chang Hu, Beth Levine, and Orson Moe, and (back) Salwa Sebti and Álvaro Fernández. Credit: UT Southwestern

Building on two decades of research, investigators at UT Southwestern have determined that "cellular housekeeping" can extend the lifespan and healthspan of mammals.

A study jointly led by Drs. Salwa Sebti and Álvaro Fernández, postdoctoral researchers in the Center for Autophagy Research, found that mice with persistently increased levels of —the process a cell uses to dispose of unwanted or toxic substances that can harm cellular health—live longer and are healthier. The study, published online today, is found in Nature.

"Specifically, they have about a 10 percent 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 Center 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 signaling pathways," said Dr. Levine, also a Professor of Internal Medicine and Microbiology who holds the Charles Cameron Sprague Distinguished Chair in Biomedical Science. "The body's natural ability to perform autophagy declines with aging, which likely contributes to the aging process itself."

Yet a crucial question remained unanswered: Is increased autophagy throughout mammalian life safe and beneficial? In other words, can autophagy extend lifespan and improve healthspan?

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 Pediatrics who holds the Makoto Kuro-o Professorship in Bone and Kidney Research, and Dr. Orson Moe, Professor of Internal Medicine and Physiology who holds The Charles Pak Distinguished Chair in Mineral Metabolism and the Donald W. Seldin Professorship in Clinical Investigation, the 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.

"These studies have important implications for human health and for the development of drugs to improve it," said Dr. Levine, who is also a Howard Hughes Medical Institute Investigator. "They show that strategies to increase the cellular housekeeping pathway of autophagy may retard aging and aging-related diseases. The results suggest that it should be safe to increase autophagy on a chronic basis to treat diseases such as neurodegeneration. Furthermore, they reveal a specific target for developing drugs that increase autophagy—namely the disruption of Beclin 1 binding to Bcl-2."

Dr. Levine's group is collaborating with Dr. Jef De Brabander, Professor of Biochemistry and a member of the Harold C. Simmons Comprehensive Cancer Center who holds the Julie and Louis Beecherl, Jr. Chair in Medical Science, and his team to synthesize such drugs. Based on the results reported in the Nature study, drugs acting through this mechanism might be expected to improve the health and prolong the lifespan of human beings.

Explore further: Researchers find newly identified immunity pathway protects mammals from virus-cause

More information: Álvaro F. Fernández et al. Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice, Nature (2018). DOI: 10.1038/s41586-018-0162-7

Related Stories

Researchers find newly identified immunity pathway protects mammals from virus-cause

March 11, 2016
Building upon earlier research, investigators at UT Southwestern Medical Center and their collaborators have identified a new innate immunity pathway that protects mammals from viral oncogenesis, the process by which viruses ...

Study links deficiency of cellular housekeeping gene with aggressive forms of breast cancer

January 30, 2015
UT Southwestern Medical Center scientists have identified a strong link between the most aggressive type of breast cancer and a gene that regulates the body's natural cellular recycling process, called autophagy.

Interference with cellular recycling leads to cancer growth, chemotherapy resistance

September 18, 2013
Overactivity of a protein that normally cues cells to divide sabotages the body's natural cellular recycling process, leading to heightened cancer growth and chemotherapy resistance, UT Southwestern Medical Center researchers ...

Peptide found to induce autophagy resulting in defense against diseases

January 31, 2013
(Medical Xpress)—A multi-disciplined team of researchers from the United States and The Netherlands has found that introducing a certain type of peptide into mice cells induces autophagy, which in turn helps in fighting ...

Scientists identify protein central to immune response against tuberculosis bacteria

January 12, 2017
UT Southwestern Medical Center researchers have identified a protein that is central to the immune system's ability to recognize and destroy the bacterium responsible for the global tuberculosis (TB) epidemic.The new finding, ...

Recommended for you

Everything big data claims to know about you could be wrong

June 19, 2018
When it comes to understanding what makes people tick—and get sick—medical science has long assumed that the bigger the sample of human subjects, the better. But new research led by UC Berkeley suggests this big-data ...

Are you sticking to your diet? Scientists may be able to tell from a blood sample

June 19, 2018
An analysis of small molecules called "metabolites" in a blood sample may be used to determine whether a person is following a prescribed diet, scientists at Johns Hopkins Bloomberg School of Public Health have shown.

Diagnosing and treating disorders of early sex development

June 19, 2018
Diagnosing, advising on and treating disorders of early sex development represent a huge medical challenge, both for those affected and for treating physicians. In contrast to the earlier view, DSD (Difference of Sex Development) ...

BPA can induce multigenerational effects on ability to communicate

June 18, 2018
Past studies have shown that biparental care of offspring can be affected negatively when females and males are exposed to bisphenol A (BPA); however, previous studies have not characterized how long-term effects of BPA exposure ...

New compound shown to be as effective as FDA-approved drugs against life-threatening infections

June 15, 2018
Purdue University researchers have identified  a new compound that in preliminary testing has shown itself to be as effective as antibiotics approved by the Food and Drug Administration to treat life-threatening infections ...

Foods combining fats and carbohydrates more rewarding than foods with just fats or carbs

June 14, 2018
Researchers show that the reward center of the brain values foods high in both fat and carbohydrates—i.e., many processed foods—more than foods containing only fat or only carbs. A study of 206 adults, to appear June ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.