Günter Blobel, known for his work on the signal hypothesis of protein targeting, has died from cancer at age 81.
Researchers find that reducing mitochondrial protein production in some animals can increase lifespan by activating a protective stress response.
May 22, 2013|
WIKIMEDIA, LOUISA HOWARDReducing mitochondrial output increases lifespan in mice and nematode worms, according to research published today (May 22) in Nature. Researchers found that reduced expression of a protein important for mitochondrial protein production triggered the mitochondrial stress response and increased lifespan in both mice and nematodes. A few known drugs affect this pathway, raising the possibility of designing longevity-enhancing therapies.
“It’s a provocative set of findings,” said Richard Miller, who studies the genetics of aging at the University of Michigan and was not involved in the research. Although previous work had indirectly suggested that changing mitochondrial function affected lifespan, “this is the first clear demonstration [that it] extends mouse lifespan,” Miller added.
It’s well known that mitochondria are linked to health. Some evidence suggests that inhibiting mitochondrial function can be harmful—as in the case of diabetes or obesity—but earlier data from nematodes and fruit flies also suggest a link to lifespan increase. The latest findings are a step toward untangling one of the current debates in the field—whether inhibiting mitochondrial function is detrimental or beneficial, said Pankaj Kapahi, who studies the genetics of aging at the Buck Institute for Research on Aging but was not involved in the study.
In order to identify genes linked to longevity in mammals, researchers led by Johan Auwerx at the Swiss Federal Institute of Technology in Lausanne combed the genomes of the BXD family of mouse strains. The average lifespan of BXD mice range from 1 year to almost 2.5 years. The researchers were able to link 3 genes to longevity variability, including mitochondrial ribosomal protein S5 (Mrps5), which encodes a protein integral to mitochondrial protein synthesis. They found that BXD strains with 50 percent less Mrps5 expression lived about 250 days longer than BXD mice with more robust Mrps5 expression.
Turning to the nematode Caenorhabditis elegans to tease out the genes’ role in controlling lifespan, the researchers found that using RNAi to knock down mrps-5 and other mrp genes increased the worms’ month-long lifespan by up to 60 percent. This suggested that inhibiting their mitochondrial function was in fact enhancing their longevity.
When Auwerx and his colleagues looked closer, they found that reducing mrps-5 expression in the worms altered the ratio of mitochondrial- versus nuclear-derived proteins involved in ATP synthesis, a situation they termed “mitonuclear protein imbalance.” This, in turn, activated the protective mitochondrial unfolded protein response (UPR). This explains how reducing mrps-5 expression can actually increase lifespan, said Auwerx. The unfolded protein response is “reparative, adaptive, and makes better mitochondria,” which help retard aging. Reducing expression of a gene involved in this stress response reversed the lifespan extension seen in worms with mrps-5 knocked down.
The researchers were also able to activate the mitochondrial UPR via pharmacological means. Dosing worms with the antibiotic doxycyline, which inhibits bacterial and mitochondrial protein translation, also activated the mitochondrial UPR and extended worm lifespans. Rapamycin, shown to enhance longevity in mice, also extended worm lifespan and induced mitonuclear protein imbalance and the mitochondrial UPR in mouse hepatocytes.
Though Auwerx and his team haven’t yet tested their hypothesis by mutating mitochondrial genes in mice, the study is “supportive of the idea that inhibiting mitochondrial function might extend lifespan”—even in mice, said Kapahi.
But mitochondrial ribosomal proteins are not to be trifled with. “There are a number of well-defined severe disorders in humans, including neonatal lethality, due to defects in those exact proteins,” observed Michael Ristow, who studies energy metabolism at the Swiss Federal Institute of Technology in Zurich. Additionally, long-term doxycycline use is toxic to humans, and rapamycin suppresses immune function so effectively that it’s given to transplant patients to prevent tissue rejection.
If mitochondria can be targeted to influence lifespan, the interventions may be tissue specific or restricted to a particular developmental window. Auwerx and his colleagues found that mitochondrial responses to doxycycline depended on tissue of origin, and knocking down mrps-5 after early development no longer affected nematode lifespan. This mirrors work in mice showing that caloric restriction most affects lifespan if it occurs within the first few weeks of life, said Miller.
Auwerx’s group is beginning to cast a wider net, looking to see whether mitonuclear protein imbalance could explain longevity induced by other means, such as caloric restriction. Auwerx hopes that the work will aid in designing a drug intervention “to pump up this response via pharmacological tools.”
In the meantime, he’s optimistic that his team has identified a “common thread” demonstrating that longevity is not affected so much by inhibiting or stimulating mitochondria, but how the organelles “deal with proteins.”
R. H. Houtkooper et al., “Mitonuclear protein imbalance as a conserved longevity mechanism,” Nature, 497:451-457, 2013.
December 20, 2013
Many types of the cancer cells have reduced mitochondrial activity. Also, many of the cancer cell types are immortal!
Will this be the cost of improving life span for humans??