Sci. Aging Knowl. Environ., 28 April 2004
Vol. 2004, Issue 17, p. ns2
[DOI: 10.1126/sageke.2004.17.ns2]


Many Roads to Ruin

Organs such as the heart and brain don't work the same way, nor do they fall apart the same way over time. Now the reasons for these differences are becoming clear

Mitch Leslie

Abstract: As researchers begin to understand the molecular faults that weaken tissues and organs over time, they are learning that some types of trouble undermine specific tissues and others affect multiple tissues. In certain tissues, for example, mature cells kill themselves in droves. In muscles, stem cells that fix injuries stop dividing. In the bones and arteries, stem cells specialize inappropriately. Putting stem cells back to work might allow scientists to repair damage. By prodding them in the bone marrow, for example, researchers might coax the damaged heart to repair itself.

Most of us only need to look in the mirror to see that aging affects different organs and tissues in myriad ways. Hair grays, skin sags, corneas cloud, bones grow brittle, paunches protrude, muscles turn to flab. After years of cataloging these responses, researchers are now beginning to tease out some of the molecular mechanisms that wear down tissues as we grow old. The findings reveal that some types of physiological blows are unique, but others hammer structures as different as blood vessels and bones. The work could soon provide a practical payoff. Although scientists are a long way from rebuilding a scarred heart or forgetful brain, they are confident that before the end of the decade, they will be able to repair some aging-related damage, buying extra time for elderly folks. However, some researchers are skeptical that focusing on specific tissues will help much in the fight against aging; instead, they favor focusing on aging's underlying causes.

Snapshots of Decay

Over the last few decades, researchers have meticulously detailed aging's physiological and biochemical toll on various tissues. Even fitness fanatics such as tennis player Andre Agassi, whose training regimen includes hours in the weight room and sprints up sand hills, can expect dwindling strength as they grow older, says muscle physiologist John Faulkner of the University of Michigan, Ann Arbor. Strength starts to wane after the age of 30, and the process accelerates in the 50s and 60s. Muscles gradually shrink, produce less force, and tire faster. Some muscle fibers disconnect from the nerves that stimulate them. The so-called fast fibers, which provide the explosive power needed to, say, bound up a flight of stairs, are most likely to unplug. Weight training can help elderly people slow the loss of strength, Faulkner says, but it can't prevent the decline.

Other faults appear in the brain and the kidneys, and in recent years scientists have started profiling the genetic changes that accompany age-related alterations in different organs and tissues. Since the late 1990s, geneticist Tomas Prolla of the University of Wisconsin, Madison, and colleagues have been using microarrays to track how gene activity fluctuates with age in the heart, brain, calf muscle, and other organs of lab animals. The results so far indicate that aging doesn't provoke a massive overhaul of gene activity. For example, Prolla and colleagues tracked 6347 genes in the mouse brain and found that only 63 decreased or increased their output a significant amount. The value can rise to about 10% in some tissues, he says--not terribly high.

Although Prolla calls the work descriptive so far, he and his colleagues have discerned some patterns. Not surprisingly, many gene-activity modifications are tissue specific. For instance, the heart turns down the activity of genes involved in fatty acid metabolism and cranks up that of genes that orchestrate carbohydrate breakdown; the muscles scale back sugar-metabolism genes. However, some responses are common to multiple tissues--ramping up the activity of genes that repair damage to DNA and shelter cells against stress, for example.

The researchers hope to identify a predictable set of alterations that will provide a better gauge of an organ or tissue's condition than an animal's age does. Some of the most useful changes might reflect the activity of a few master genes that drive deterioration. Sorting these from the thousands of followers will be tough, Prolla says. However, he and his colleagues now have a long list of candidates, and they're disabling or ramping up the genes one at a time in experimental animals to determine the effect on health.

Better to End It All?

Millions of cells in the body kill themselves every day, but don't weep for them. The die-off is deliberate and usually beneficial, culling damaged cells that could turn cancerous--although the attrition can be harmful. Recent research reveals that the rate of cell suicide, known as apoptosis, soars in certain older tissues. Confirming this age-associated increase was a challenge, says cell biologist Brian Herman of the University of Texas Health Science Center in San Antonio. Although many studies had detected evidence of cell suicide--such as broken DNA--in tissue from elderly animals, the same changes sometimes occur in cells that die of other causes, says Herman. So in 2002, he and his colleagues focused on caspases, proteins that prod cells to off themselves and are the molecular equivalent of a smoking revolver found in the victim's hand. They measured the amounts of various caspases in the livers, lungs, and spleens of young, middle-aged, and elderly rats and found that the activity of several killer proteins increases with age. Other work suggests that self-slaughter rises most in tissues where cell turnover is rapid, such as the liver and lung, and it climbs only slightly in more stable organs, such as the brain, Herman says.

Why the rate of cell suicide increases in the elderly remains mysterious. Cranking up apoptosis could be beneficial, helping eliminate a growing number of defective cells. On the other hand, increased apoptosis could disrupt tissues and rub out stem cells needed for injury repair. Ailments such as Parkinson's and Alzheimer's diseases might involve excess apoptosis of brain cells, Herman says (see "Detangling Alzheimer's Disease" and "Murder on the Parkinson's Express"). He and other researchers hope to resolve the question by tweaking the apoptosis pathways in experimental animals and measuring the effect on longevity.

A Failure to Regenerate

Seared by sunlight, blasted by wind, scratched, and scuffed, the skin goes through cells faster than teenagers go through outfits. And even stolid organs such as muscles require a supply of new cells. The inability to provide these replacements saps tissues throughout the body, many researchers argue. "If it [the mechanism] is not universal, it's close," says neurologist Thomas Rando of Stanford University.

Take the muscles. Jogging 8 kilometers gives the heart a salutary workout and unleashes feel-good endorphins, but it also rips muscle fibers in the legs. No problem for young runners, because muscle stem cells slither to the rescue. Injury spurs these so-called satellite cells to divide, and their progeny patch existing fibers or merge to form new ones. But as we grow older, repairing this damage gets harder and harder. By comparing recovery ability in young and graying mice, Rando and colleagues showed why this capacity falters with age, results they published last November in Science.

Although the number of satellite cells doesn't decline with age, they become reluctant to divide, the researchers found. Compared with cells from youthful rodents, older satellite cells carried less of the activated form of a protein called Notch, which helps orchestrate formation of muscles and other organs during embryonic development (see Miller and Emerson Perspective). Damage also spurred young muscles to exude Notch's activator, Delta-1, but elderly tissue produced little Delta-1. To gauge whether pumping up the amount of activated Notch would restore repair ability, Rando's team injured muscles of old and young mice, then activated Notch using an antibody that jams it in the "on" position. In response to damage, cells from elderly mice produced about the same number of new fibers as did young cells. The results show that restoring youthful function is possible, says Rando. The approach might lead to treatments that encourage muscle healing. Glitches in the Notch pathway could underlie regeneration failures in other tissues, he says, but nobody has tested the idea.

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Strength in numbers. After researchers activate the Notch protein, old satellite cells (bottom row) can make as many muscle fibers as younger cells (upper row) do. The glowing spots indicate dividing cells. [Credit: I. M. Conboy et al., Science 302, 1575 (2003)]

Repair failure is only one of the defects that sap strength in older muscles, Rando notes. The muscles of elderly folks also shrink and produce less force. Because satellite cells might have multiple jobs, Rando and his colleagues want to determine whether their lethargy also causes age-related atrophy.

Tuckered-Out T Cells

Cells that are unwilling to divide might cause problems elsewhere in the body. These layabouts could even stir up trouble beyond their home tissue, says immunologist Rita Effros of the University of California, Los Angeles. When researchers repeatedly prod T cells to duplicate in the culture dish, the cells eventually stop dividing and enter a state known as replicative senescence (see "More Than a Sum of Our Cells"). The same stagnation might occur as we age, Effros says. Large numbers of T cells from older folks show telltale molecular signs of replicative senescence; for instance, they lack the CD28 cell surface receptor (see "Immunity Challenge").

Senescent cells cause problems because they don't necessarily settle into a quiet retirement (see "Faustian Bargain"). They release molecules that might spark the widespread inflammation that triggers heart disease and other chronic illnesses. Senescent T cells might also goad bone-dissolving cells into action, contributing to skeletal weakening. "There's more and more evidence that immune cells are directly involved in the pathologies of aging," Effros says.

Researchers drive cultured T cells to senescence by continually stimulating them with a fragment of a pathogen. Something similar might happen in the body because of chronic infections with Epstein-Barr virus, cytomegalovirus, or HIV. Although only a small fraction of the population gets HIV, almost everyone catches Epstein-Barr virus and cytomegalovirus in childhood, says Effros. The viruses can lurk in the body, provoking repeated responses from the immune system. Because each T cell targets a particular pathogen, cellular senescence leaves the immune system defenseless against that invader. The attrition could help explain why elderly folks are more vulnerable to infections, says Effros.

Identity Crisis

Whereas muscle stem cells and T cells fail to divide, some grizzled stem cells suffer confusion about what to become. The mix-up could provoke or worsen disparate age-related diseases such as atherosclerosis and osteoporosis, says rheumatologist Linda Demer of the University of California, Los Angeles (see "The Plot Thickens on Thin Bones"). For example, the wall of a diseased artery can be a tissue junkyard, cluttered with marrow, cartilage, fat, and bits of bone. In November, Demer and colleagues showed that stem cells captured from artery walls can produce these types of tissue. Although stem cells from bone marrow, which serves as the natural source for multiple cell types, have not committed to a particular fate, scientists expected that stem cells from the vessel wall would specialize selectively. Demer argues that a similar response occurs in the skeleton, where precursors mature into mushy, fatlike cells. In a study published earlier this year, her group showed that fats galvanize bone-gnawing cells called osteoclasts. What happens is "hardening of the soft tissues and softening of the hard tissues," Demer says.

Triggering the stem cell mix-up is excess fat sloshing around in the blood. It gets oxidized and infiltrates artery linings and bones. Oxidized lipids spark an immune reaction, which in turn activates stem cell specialization. In the artery wall, the cells build bone to seal off what they mistake for an infection. Instead, the skeletal fragments can worsen atherosclerosis by stiffening the vessel. In the skeleton, too, blood lipids are the villains, Demer notes, and we already have good ways to rein them in--although many Americans are loath to put down the doughnuts and get off the couch. However, says Demer, researchers can now tweak the stem cells' chemical environment in the culture dish and identify compounds to keep the precursors from going astray. "Having cells go along the right lineage is part of avoiding aging," she says.

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The fat connection. Lipids in the blood set off stem cell responses that weaken bone and harden arteries. [Source: Linda Demer; Illustration: Julie White]

This Old Heart

Nudging stem cells along the right pathway could also help rebuild tissues battered by aging--and such treatments are closer than many people realize, some scientists say. For instance, heart attack patients will be regrowing damaged muscle before the end of the decade, researchers in the field say. Cells that can refurbish a broken heart dwell in the bone marrow, and several teams have already shown in clinical trials that the cells can strengthen damaged hearts (see Couzin and Vogel Science Article). Now, cardiologists want to determine how to coax the best performance from these repair crews without triggering side effects.

Getting cells to make muscle in a culture dish is easy. Steep immature bone marrow cells in the right brew, and after a few days their syncopated pulsing signals their transformation into heart cells, says cardiologist Jay Edelberg of Cornell University's Weill Medical College in New York City. The question is why stem cells don't normally refurbish the heart in older patients. One possible reason, Edelberg says, is scarcity of a chemical called platelet-derived growth factor (PDGF), which pushes cells to specialize.

To test that hypothesis, Edelberg and colleagues injected stem cells, PDGF, or a combination of the two into the hearts of rats, then simulated a heart attack by temporarily tying off an artery. As the researchers reported in February, all three treatments roused stem cells to spawn new muscle tissue. Moreover, when the researchers measured the rats' maximum running speed on a treadmill, they found that treated rodents scurried between 10% and 30% faster than control animals did. The cells didn't fully integrate with existing heart tissue, a flaw that could lead to erratic rhythms, but the work suggests that chemical cajoling can spur heart repair. "The real thing you want are drugs that turn on the body's ability to do this. We'll see them within 5 years," Edelberg predicts.

Time to Zoom Out?

Some researchers are skeptical that focusing on individual tissues will add years to our lives. . The biggest killer of people is heart disease, which suggests that this organ doesn't age gracefully. But patching a wounded heart will only spare us to die from some other cause, says molecular biologist Arlan Richardson of the University of Texas Health Science Center in San Antonio, because aging erodes the whole body. We won't make much progress against these killers without attacking the underlying causes of aging and stopping the deterioration in the first place. "You need to slow aging overall, not tinker with individual tissues," he says.

Rando disagrees. The piecemeal approach might help us identify these broader causes, he says: "I would argue that the deeper one searches into any tissue, the closer one will get to mechanisms that are general and that apply to many tissues." The truth will come out as researchers test methods to fortify the heart, bulk up the muscles, and keep stem cells on the straight and narrow. Their findings will tell us whether we can fight aging one tissue at a time.

April 28, 2004

Mitch Leslie, a science writer in Albuquerque, New Mexico, hopes that his brain will age more gracefully than his hair.

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Citation: M. Leslie, Many Roads to Ruin. Sci. Aging Knowl. Environ. 2004 (17), ns2 (2004).

Science of Aging Knowledge Environment. ISSN 1539-6150