Quote

“Instead of studying the diseases of aging — Parkinson’s disease, Alzheimer's disease, cancer, stroke, cardiovascular disease, diabetes — one by one, we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases,” said Walker, a member of UCLA’s Molecular Biology Institute. “We are not there yet, and it could, of course, take many years, but that is our goal and we think it is realistic.

“The ultimate aim of our research is to promote healthy aging in people.”

The fruit fly, Drosophila melanogaster, is a good model for studying aging in humans because scientists have identified all of the fruit fly’s genes and know how to switch individual genes on and off. The biologists studied approximately 100,000 of them over the course of the study.

Lead author Matthew Ulgherait, who conducted the research in Walker’s laboratory as a doctoral student, focused on a cellular process called autophagy, which enables cells to degrade and discard old, damaged cellular components. By getting rid of that “cellular garbage” before it damages cells, autophagy protects against aging, and AMPK has been shown previously to activate this process.

Ulgherait studied whether activating AMPK in the flies led to autophagy occurring at a greater rate than usual.

“A really interesting finding was when Matt activated AMPK in the nervous system, he saw evidence of increased levels of autophagy in not only the brain, but also in the intestine,” said Walker, a faculty member in the UCLA College. “And vice versa: Activating AMPK in the intestine produced increased levels of autophagy in the brain — and perhaps elsewhere, too.”

Many neurodegenerative diseases, including both Alzheimer’s and Parkinson’s, are associated with the accumulation of protein aggregates, a type of cellular garbage, in the brain, Walker noted.

“Matt moved beyond correlation and established causality,” he said. “He showed that the activation of autophagy was both necessary to see the anti-aging effects and sufficient; that he could bypass AMPK and directly target autophagy.”

Walker said that AMPK is thought to be a key target of metformin, a drug used to treat Type 2 diabetes, and that metformin activates AMPK.

The research was funded by the National Institutes of Health’s National Institute on Aging (grants R01 AG037514 and R01 AG040288). Ulgherait received funding support from a Ruth L. Kirschstein National Research Service Award (GM07185) and Eureka and Hyde fellowships from the UCLA department of integrative biology and physiology.

Quote

“Cell survival is dependent upon the ability of the cell to reduce and recycle by a mechanism called autophagy,” said William Dunn Jr., a professor of anatomy and cell biology in UF’s College of Medicine and senior author of the study, which was published online this month in the journal Rejuvenation Research. “When a cell is under stress, autophagy is turned on to clean up the cell by removing damaged cellular components, while recycling building blocks necessary to rebuild the cell. It’s there to protect the cell. But in aged cells, they’re basically not able to adjust to stress as well.”

UF scientists studied 22 young and old rats, comparing those allowed to eat freely with those fed a low-calorie, nutritious diet. The stress of a low-calorie diet was enough to boost cellular cleaning in the hearts of older rats by 120 percent over levels seen in rats that were allowed to eat what they wanted. The diet had little or no effect on younger rats.

“Autophagy is a housekeeping mechanism that keeps cells free of damaged and thereby detrimental mitochondria and other toxic materials while recycling their building blocks – nutrients needed by the cell,” said Stephanie Wohlgemuth, a lecturer in UF’s department of aging and geriatrics and the study’s lead author. “So if that process is maintained with age — or even increased — that can only be beneficial.”

To determine how dietary restriction boosted cells’ ability to reduce the toxic trash, the scientists studied how the amount of certain proteins changed with the rats’ age and diet. They found that some proteins responsible for degrading the damaged parts of the cell by autophagy were more abundant in older, calorie-restricted rats.

Boosting autophagy is especially important in the heart, a vital organ packed with mitochondria, Wohlgemuth said. Swift disposal of damaged cellular components is essential to maintaining an abundance of healthy heart cells as we age.

“Cardiac cells have lost the capability to divide readily to replace dying cells. So the maintenance of the cells’ survival mechanisms is crucial for the heart,” Wohlgemuth said.

Now that some of these proteins have been identified, UF researchers say the next step is to figure out how the proteins can be activated without inflicting dietary stress.

“What if we bypass the caloric restriction and find a way of increasing autophagy?” asked Dunn. “That is, instead of starving yourself you can find another way of enhancing autophagy that will allow the enhanced removal of various damaged organelles that accumulate in aged cells.”

Dr. Ulf Brunk, a professor emeritus of experimental pathology at Linköping University in Sweden, said the study builds on past research showing that removal of toxic mitochondria may extend life in a variety of mammals.

Quote

Abstract

Disruption of autophagy--a key homeostatic process in which cytosolic components are degraded and recycled through lysosomes--can cause neurodegeneration in tissue culture and in vivo. Upregulation of this pathway may be neuroprotective, and much effort is being invested in developing drugs that cross the blood brain barrier and increase neuronal autophagy. One well-recognized way of inducing autophagy is by food restriction, which upregulates autophagy in many organs including the liver; but current dogma holds that the brain escapes this effect, perhaps because it is a metabolically privileged site. Here, we have re-evaluated this tenet using a novel approach that allows us to detect, enumerate and characterize autophagosomes in vivo. We first validate the approach by showing that it allows the identification and characterization of autophagosomes in the livers of food-restricted mice. We use the method to identify constitutive autophagosomes in cortical neurons and Purkinje cells, and we show that short-term fasting leads to a dramatic upregulation in neuronal autophagy. The increased neuronal autophagy is revealed by changes in autophagosome abundance and characteristics, and by diminished neuronal mTOR activity in vivo, demonstrated by a reduction in levels of phosphorylated S6 ribosomal protein in Purkinje cells. The increased abundance of autophagosomes in Purkinje cells was confirmed using transmission electron microscopy. Our data lead us to speculate that sporadic fasting might represent a simple, safe and inexpensive means to promote this potentially therapeutic neuronal response.