Sci. Aging Knowl. Environ., 5 April 2006
Vol. 2006, Issue 7, p. nf9
[DOI: 10.1126/sageke.2006.7.nf9]


Environmental Movement

Researchers are discovering how the molecules in cells' surroundings contribute to aging--and how tweaking them might rejuvenate tissues

Mitch Leslie

No cell is an island. Whether it migrates or stays put, stretches or contracts, divides or dies depends on cues from its surroundings. As they make these decisions, cells heed the extracellular matrix (ECM), the mesh of proteins, sugars, and other molecules that supports our tissues. Researchers long dismissed the ECM as mere filler, but they have discovered that age-related changes to its structure and composition promote cancer, undermine the heart, and might trigger other scourges of old age. Although scientists are just beginning to tease apart the molecular mechanisms that drive ECM deterioration, they hope to apply the knowledge to refurbish fraying tissues.

Enter the Matrix

Without the ECM, we'd be amoebas. The network shapes the body and holds it together. Cartilage, skin, and bone are mainly matrix. The ECM also keeps our organs working. For example, it anchors heart muscle cells and prevents them from damaging themselves by stretching too far. In the ECM, strands of collagen provide strength; another protein, elastin, confers stretchiness. These molecules interweave with proteoglycans, proteins festooned with carbohydrates such as chondroitin sulfate.

Figure 1
View larger version (162K):
[in this window]
[in a new window]
Support system. Cartilage cells embedded in a matrix of collagen and proteoglycans. [Credit: Innerspace Imaging/Photo Researchers Inc.]

The ECM is not the biological equivalent of mortar in a wall, as scientists once thought. An intricate interplay between the cell and its environment shapes both. Cells extrude and mold the ECM's components. In turn, cells' behavior depends on chemical signals from the ECM and even on how strongly matrix fibers tug on them. The ECM teems with so-called matricellular proteins that play no structural role but that serve as messengers, influencing whether cells grow and how tightly they adhere to matrix proteins, for example. Studding the cell membrane are integrins, receptors for gathering ECM messages. Recent results suggest that even cells with direct lines of communication rely on the ECM as a "back channel." A brain cell signals its neighbor by spilling neurotransmitters into the synapse that connects them. But the cell can spread its influence by releasing neurotransmitters into the ECM, notes neuroscientist James Roberts of the University of Texas Health Sciences Center in San Antonio. The molecules seep through the matrix and goad distant cells. "It's a parallel system to the wiring in the brain," says Roberts.

Aging's Toll

To see that aging hammers the ECM, take a look in the mirror. Drooping jowls, flaccid eyelids, and furrowed foreheads betray ECM deterioration. (Don't see them yet? You will.) Skin wrinkles and sags as we grow older in part because it packs in less collagen. Insidious ECM changes underlie many of the diseases of aging, including heart disease, cancer, and arthritis. For example, the plaques that can eventually trigger a heart attack hatch in the ECM of blood vessels.

Researchers haven't cataloged all the age-related alterations in the ECM, says geriatrician May Reed of the University of Washington, Seattle, but the results so far indicate that the changes vary from organ to organ. Unlike the skin, the heart and blood vessels bulk up with collagen (1). Cartilage in the joints thins, calcifies, and stiffens (see Loeser Perspective). This hardening of the cartilage stems partly from the accumulation of advanced glycation end products (AGEs), sticky outgrowths that form when glucose reacts with proteins and other large molecules (see "Wake Up and Smell the Maillard Reaction"). AGEs affixed to the ECM might even spur cells to kill themselves (see Obrenovich and Monnier Perspective).

Like Madonna, the ECM is continually remaking itself, and this reinvention might unleash other age-related damage. Instead of personal trainers and Kabbala coaches, the ECM relies on matrix metalloproteinases (MMPs), a coterie of 25 enzymes that chop up worn collagen strands and other molecules so they can be replaced. The catch is that the protein fragments, known as matricryptins, also prod cells, says Ladislas Robert, a professor emeritus and biochemist at the University of Paris in France. Some matricryptins exert positive effects, such as helping manage cell growth, but others can injure tissues (2, 3). Snippets of fibronectin, a protein that helps cells link to the ECM, can incite inflammation. Moreover, because these cuttings boost fibronectin production, they might trigger a vicious circle in which matricryptins spur increased fibronectin output, which in turn leads to more matricryptins and greater ECM damage, Robert says.

The Ecology of Cancer

Researchers are still piecing together how the ECM's changes over time promote illness. One alteration appears to disable a key defense against cancer. Ironically, this baneful outcome might stem from a mechanism to avert cancer early in life.

Cancer isn't just a matter of accruing specific DNA glitches, many studies have shown. The right surroundings can stymie tumor growth, even if cells carry all the necessary mutations for malignancy (4). However, this protection can break down because of the actions of other, worn-out cells, according to work by cell biologist Judith Campisi of Lawrence Berkeley National Laboratory in California and colleagues (see "Dangerous Liaisons"). The trouble begins with cells that have divided numerous times. Each time a cell reproduces, its telomeres--the caps that protect the tips of chromosomes--shrink. Cells with short telomeres pose a threat because they are prone to DNA damage that can spur rampant growth. To protect the body, some cells that have divided a certain number of times enter a state called senescence, in which they lose the ability to split (see "More Than a Sum of Our Cells"). Senescence is an adaptation that prevents tumors from sprouting early in life, Campisi and colleagues argue.

But senescence might cause problems later by eating away the ECM. Senescent cells pepper tissues throughout the body, and they accumulate with age. Instead of whiling away their retirement, the cells spill MMPs and inflammation-promoting compounds that weaken the ECM. If other potentially cancerous cells are nearby, this fraying might allow them to grow and spread through the once-confining matrix (5). Findings from Campisi's group indicate that senescent cells spur other, genetically damaged cells to seed tumors (see "Faustian Bargain") and boost cells' ability to infiltrate neighboring tissues (see "Led Astray").

Figure 2
View larger version (113K):
[in this window]
[in a new window]
Cellular jailbreak. A) The extracellular matrix pens in a cancer cell (blue). B) Enzymes from senescent cells (red) erode the matrix. C) Further deterioration allows cancer cells to break out of confinement. [Illustration: Christopher Bickel/Science]

Stunted Vessels and Heavy Hearts

Another deficiency traceable to alterations in the ECM is a reduced capacity to sprout new blood vessels (see Reed and Edelberg Perspective). Angiogenesis, or blood vessel growth, requires matrix proteins to guide the cells that will construct the new pipes into position. Hindering angiogenesis undermines wound healing and can thwart repair of cardiac muscle after a heart attack, says Reed. Researchers "are still groping" to find out which ECM denizens leave angiogenesis in the lurch, says Reed. Two suspects are the matricellular proteins thrombospondin and SPARC, although their impact is uncertain (6, 7). If researchers can pin down the culprits, they still need to answer a broader question, Reed says: "What we don't know is whether impaired angiogenesis in aging is a bad thing [overall]." It might prevent tumors from acquiring the blood supply they need to spread.

Our hearts get bigger as we get older--but not because we're growing more compassionate. The ventricles swell, and their walls thicken as collagen piles up in the ECM. Although this protein overload gradually saps the heart's strength, the organ usually continues to deliver enough blood for many years, says molecular biologist Merry Lindsey of the University of Texas Health Sciences Center in San Antonio. However, it loses its resilience, so that a heart attack or other stress can cause enough damage for the muscle to fail.

A study last year by Lindsey and colleagues suggests that the older heart fights the collagen buildup but can't stop it. The researchers measured the activity of eight MMP varieties in hearts from young, middle-aged, and old mice. They sorted heart proteins into insoluble and soluble sets. The insoluble group holds the established ECM components, whereas the soluble fraction includes newly formed ECM and matrix that has been broken down. The soluble fraction indicates how rapidly the ECM is being renovated. Among the insoluble proteins, activity of three MMPs shot up in elderly mice (8). But among the soluble proteins, the activity of five MMPs fell with increasing age. Insoluble collagen amounts declined, the researchers found, but quantities of soluble collagen surged. The results suggest that aging mice speed the breakdown of insoluble collagen in the ECM by cranking up MMP activity there. But increased collagen quantities in the soluble portion suggests that the heart responds by making even more matrix. Apparently, even the amped-up MMPs in the insoluble portion of the ECM can't offset the production of new protein, and the mice lose the race against collagen buildup, Lindsey says.

Nipped in the Bud

Another way the ECM can make life miserable for the old is by stalling the regeneration of damaged tissue. Such a hostile environment seems to prevail in Parkinson's disease, says Roberts. The illness results because large numbers of neurons die in a brain region called the substantia nigra (see Parkinson's Disease Case Study and Andersen Review). These neurons manufacture the neurotransmitter dopamine, without which the brain can't control movement. What puzzles researchers is why the brain doesn't replace the lost neurons, Roberts says. New cells migrate into the right region, but they don't mature properly. One possible reason, Roberts and colleagues discovered, is that as we age, the ECM in this part of the brain becomes unfriendly to new neurons. Chondroitin sulfate, one of the carbohydrates that decorates ECM proteins, accumulates and prevents fresh cells from specializing into neurons, says Roberts.

The Matrix Reloaded?

Researchers want to learn how to refurbish the ECM in older people and stave off killers such as heart disease, cancer, and arthritis. Instead of battling tumors with toxic radiation and chemotherapy, for instance, doctors might turn to compounds that fortify the ECM and prevent a renegade cell from growing out of control. Ironically, medical advances have made the need for such therapies more urgent, notes Robert. From statins to angioplasties, doctors have plenty of weapons for keeping arteries open. As a result, he says, more older people are dying from heart failure because the debilitated organ can't pump blood through increasingly stiff vessels. Heart weakening and vessel stiffening stem from changes in the ECM, and current treatments can't reverse them. The question looming over the field, Reed says, is whether rejuvenating the ECM will return older cells to their youthful fettle, or whether they are irreparably damaged. Further research might reveal whether exposing cells to good influences will make them young again. If so, we might all benefit from the fact that our cells aren't all at sea.

April 5, 2006

A writer in rainy Portland, Oregon, Mitch Leslie doesn't heed outside influences.

  1. O. Uspenskaia, M. Liebetrau, J. Herms, A. Danek, G. F. Hamann, Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci. 5, 37 (2004). doi:10.1186/1471-2202-5-37 [CrossRef][Medline]
  2. G. E. Davis, K. J. Bayless, M. J. Davis, G. A. Meininger, Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am. J. Pathol. 156, 1489-1498 (2000).[Medline]
  3. J. Labat-Robert, Cell-matrix interactions in aging: Role of receptors and matricryptins. Ageing Res. Rev. 3, 233-247 (2003). doi:10.1016/j.arr.2003.10.002
  4. P. A. Kenny and M. J. Bissell, Tumor reversion: Correction of malignant behavior by microenvironmental cues. Int. J. Cancer 107, 688-695 (2003). doi: 10.1002/ijc.11491 [CrossRef][Medline]
  5. J. Campisi, Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors. Cell 120, 513-522 (2005). doi:10.1016/j.cell.2005.02.003 [CrossRef][Medline]
  6. P. Puolakkainen et al., Compromised production of extracellular matrix in mice lacking secreted protein, acidic and rich in cysteine (SPARC) leads to a reduced foreign body reaction to implanted biomaterials. Am. J. Pathol. 162, 627-635 (2003). [Medline]
  7. M. J. Reed et al., Enhanced angiogenesis characteristic of SPARC-null mice disappears with age. J. Cell. Phys. 204, 800-807 (2005). doi:10.1002/jcp.20348 [CrossRef][Medline]
  8. M. L. Lindsey et al., Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function. Cardiovasc. Res. 66, 410-419 (2005). doi:10.1016/j.cardiores.2004.11.029 [Abstract/Free Full Text]
Citation: M. Leslie, Environmental Movement. Sci. Aging Knowl. Environ. 2006 (7), nf9 (2006).

Science of Aging Knowledge Environment. ISSN 1539-6150