As the role of senescence in health and disease gains prominence, researchers new to the phenomenon are beginning to look for connections to their own work. HHMI investigator Joan Steitz of Yale University has been fascinated by how small RNA molecules control the activity of genes. Now, she's starting to look at how this capability ties to senescence.
One particular type of small RNA molecules, called microRNAs, control how much protein a cell makes from a messenger RNA (see “The Macro World of MicroRNA,” page 20). In an actively growing and dividing cell, microRNAs dampen the amount of protein the cell makes. But microRNAs do the opposite and amplify protein production when cells are in a state called quiescence, Steitz's group has found. Like senescent cells, quiescent cells don't divide. But, unlike senescent cells, they can reactivate and start growing and dividing again. “We want to know why microRNAs do one thing when cells are rapidly proliferating and another thing when they withdraw from the cell cycle,” says Steitz. She is now collaborating with Yale colleague Daniel DiMaio to understand how microRNAs work in senescent cells. “Would the same kind of controls be going on in senescent cells?” she asks. “Would it be a different protein that is associated? We don't know.”
In addition to the activity of genes, senescence might tie to the activities of mitochondria. These structures generate power in cells, and David Chan at the California Institute of Technology, who was named an HHMI investigator in spring 2008, scrutinizes how mitochondria merge and divide. He's curious how this dance influences energy production and how missteps might trigger illness.
Mitochondria accumulate mutations in their DNA over a lifetime. As the glitches pile up, they can cause mitochondria to produce less energy or work less efficiently. It's particularly troublesome for the brain and muscles, heavy users of energy. A blackout in cellular energy production may also contribute to gray hair, weak bones, and other age-related changes.
Chan has found that the many mitochondria in a cell split and join, allowing them to mix and redistribute copies of mitochondrial DNA, which means any particular cell is unlikely to remain stuck with a large number of faulty mitochondria. “Fusion is potentially a protective mechanism,” says Chan.
Chan suggests that a connection between mitochondrial dynamics and cellular aging could exist. Old cells may have deficiencies in mitochondrial fusion that help mutations build up, he says. Faults in this process could be particularly important in neurodegenerative diseases. Evidence already links problems in mitochondria to Alzheimer's disease, Parkinson's disease, and Lou Gehrig's disease (amyotrophic lateral sclerosis). Recent studies even suggest that a gene involved in mitochondrial dynamics is crippled in some inherited forms of Parkinson's disease. Chan plans to dig deeper into these disease connections. With this new scrutiny, cellular aging could step farther into the spotlight as a key component of many diseases.