1. Longevity
During autophagy-literally "self-eating"-cells deliver cytoplasmic constituents, including
whole organelles, to the lysosome for degradation.
By Jill Adams(juadams@the-scientist.com) | May 9, 2005
Courtesy Edward T.W. Bampton, Gerry Smith, Alena Pance
During autophagy-literally "self-eating"-cells deliver
cytoplasmic constituents, including whole organelles, to the
lysosome for degradation. This crucial recycling process kicks
in during gross developmental changes and times of nutrient
deprivation. New work may place it within cellular aging
pathways as well.
Characterized morphologically by Christian de Duve in the
1960s, autophagy was a natural extension of his Nobel Prize-winning
work on lysosomes. Veteran researchers in a once
obscure field point to the discovery of the molecular machinery
a decade ago-autophagy gene products that drive the process-as
a boost to their own work. More recently, the linkage of one
of these genes with tumorigenesis placed autophagy under a
new spotlight and is credited with widening the investigative
pool. Now scientists are finding evidence-both circumstantial
and causal-that autophagy is a key mechanism in how certain
manipulations, namely mutations in insulin signaling and
caloric restriction, promote longevity.
Autophagy often gets overlooked as "just housekeeping,"
says Beth Levine, professor of internal medicine at the
University of Texas-Southwestern Medical Center at Dallas. In
fact, she says, failures in keeping house likely contribute to
diseases such as cancer and neurodegeneration. In addition,
autophagy wanes with age for reasons that aren't yet clear,
says Levine, and is "mechanistically important" in aging itself.
FROM FEAST TO FAMINE
When food is scarce, autophagy gets turned on as a survival mechanism. When food is moderately
restricted for a long time, organisms from worms to mammals live longer. Ettore Bergamini, professor of
pathology at the University of Pisa, Italy, provides some evidence that increased autophagy may
accompany calorie-restricted life extension. In rats subject to caloric restriction, autophagic efficiency is
maintained in old age and rats live longer.1
"The problem of aging is free radical production and imperfection of the cell-repair mechanisms," says
Bergamini. Perhaps more general contractor than housekeeper, autophagy is a "second-line defense"
against the maintenance challenges of cells. "One hundred million free radicals are generated per day in
our body," he says. "Ten thousand DNA lesions per day per cell are produced." Defects that slip past the
front-line defenses-DNA repair systems and proteosomal degradation-are refurbished, and damaged
organelles are removed.
Also, if autophagy falls off in age, then the detritus of cell metabolism accumulate more readily. By
degrading damaged organelles that generate reactive oxygen species, autophagy fits nicely into the
mitochondrial theory of aging. The capacity of autophagy to catabolize whole organelles, and mitochondria
in particular, may be its strongest selling point in terms of being an antiaging mechanism.
Mitochondria are a frequent target of autophagy, says John Lemasters, professor of cell and
developmental biology at the University of North Carolina. "They will sort of wear out," he says. "In
nonproliferating tissues like brain, heart, and liver, the mitochondria turn over every 10 to 25 days." This
rate is accelerated by nutrient deprivation and glucagon, both stimulants of autophagy.
Lemasters studies specific changes in damaged mitochondria that may invite their degradation.
"Autophagy becomes a mechanism to remove the ones that ought to be eliminated," he says. Damaged
mitochondria might generate even more free radicals to "do mischief," which can be especially
treacherous in nondividing tissues like heart and brain "where age-dependent effects really manifest
themselves quite strongly." Age-related diseases of these tissues-cardiomyopathy and neurodegeneration-have
been implicated as disorders of autophagy.
4. Other pathways have certainly been implicated in the lifespan extension induced by calorie restriction.
Fasting upregulates expression of sir-2 in yeast and worms, and SIRT-2 in mice, and the resulting proteins
may help mobilize glucose for use in the cell.7 At present, no one has tried to link autophagy to the sir-2
pathway, although Levine admits that she's pondered the notion.
Aging is ill defined and certainly multifactorial. The appeal of autophagy to ameliorate normal aging is its
capacity as a jack-of-all-trades repair mechanism in the cell. "I believe that the induction of autophagy in
caloric restriction-or loss-of-function mutation in insulin signaling-leads to increased degradation of
damaged mitochondria and reduction of oxidative stress," says Levine. "And that's probably a downstream
pathway that's in common to all these life extension phenotypes."
Courtesy Dan Klionsky
In yeast, the Tor kinase exerts a negative regulatory effect on autophagy when cells are growing under
nutrient-rich conditions. Most of the proteins required for autophagy are constitutively expressed. When
starvation occurs, the Tor kinase is inactivated allowing other downstream effectors, most likely
phosphatases and kinases, to modulate such proteins as Atg13 which in turn modulates the key kinase
Atg1, required for autophagy.
Autophagy has not been a target in aging research for long. And while Klionsky appreciates the attention
autophagy is receiving now, he doesn't discount the value of working "in the shadows" before. As one of
only a few labs working in yeast, he recounts, "We were going along, making a lot of progress, getting the
genes identified." Then Levine's 1999 paper came out implicating autophagy in tumor suppression.8 The
response was a flurry of work that Klionsky jokingly compares to party crashers eating all the food and
leaving a mess. "Since then, people have solidified the cancer connection," he says. At present, autophagy
is implicated in controlling neurodegeneration, myopathy, pathogen invasion, and lifespan. Klionsky adds,
"Now you're seeing papers coming out in Science, Nature, and Cell."