Michael D West Introduction to Aging

In the course of human development, one observes a progressive increase in body size and maturation until sexual maturity is attained. Having reached this summit, the body then shows a progressive degeneration with the passage of time, a phenomenon frequently referred to as aging. The reason for the maturation phase may seem obvious, but why we age has remained a conundrum. As G.C. Williams once observed, "It is indeed remarkable that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed."1 In this chapter, we will explore one model for the cellular basis of this decline in connective tissues. We will focus in on a candidate mediator of age-related connective tissue degeneration, interstitial collagenase, to which we will hereafter refer to as "collagenase".

The aging of skin provides an important model for biological gerontology. The connective tissue of the dermis is readily accessible for studies from individuals of all ages. Generally a small punch biopsy is sufficient to supply cultures of fibroblasts, keratinocytes, or sections for histology. Such studies demonstrate pronounced changes in histology with age, alterations that share many features with similar changes occurring in other tissues in the body.2 These observations suggest that the study of aging skin could yield important clues to the pathogenesis of other age-related connective tissue disorders, and perhaps, aging in general.

Skin, however, is unique it its exposure to relatively high levels of ultraviolet radiation. Therefore, a distinction is usually drawn between those changes in the skin attributed to long-term exposure to solar radiation (actinic skin damage) and those independent of such extrinsic causes (intrinsic skin aging). Much of this discussion will focus on intrinsic mechanisms, although, there may be considerable overlap between the two pathways.3 We will begin by reviewing what is known of the histological alterations in aging dermis and then discuss the possible role of the aging fibroblast in this process. We will then review recent insights regarding the altered gene expression of senescent cells, and examine the transcriptional regulation of collagenase. Finally, we will examine possible targets for pharmaceutical intervention.

Histological Changes in the Aging Dermis

The aging of connective tissues is associated with the destruction of histological architecture (morpholysis) often resulting in an associated loss of function (physiolysis). Morphological changes during cutaneous aging include: dermal atrophy, wrinkling, elastolysis,

Collagenases, edited by Warren Hoeffler. ©1999 R.G. Landes Company.

and a loss of subcutaneous fat. Dermal atrophy, as opposed to epidermal, is believed to play the most significant role in the visible changes, with critical alterations occurring in several components of the extracellular matrix (ECM).

The dermis is comprised of a complex of ECM molecules, of which collagen is the most abundant component.4,5 There is a striking loss of collagen with age. The collagen content of the dermis is estimated to decrease at about 1% per year during adult life.6 In particular, there is a loss of the fascicular collagen fibrils and an increase in fibrils that show a disorganized and granular morphology. The altered appearance of the collagen fibers has also been attributed to the loss of intercalated proteoglycan7 in particular, a loss of hyaluronic acid and dermatan sulfate.8 However, since collagen alone imparts most of the tensile strength to the skin, the degeneration of structural integrity of collagen fibers may underlay the pronounced fragility of elderly skin.

In addition, elastin comprises some 2% of the protein content of the dermis.9 It is a fibrous structural protein that supplies the skin and other connective tissues with the capacity for elastic recoil. Elastin fibers are markedly disintegrated in the course of both actinic and intrinsic aging.10,11 By the age of 70, most fibers show a decrease in number and diameter, and appear fragmented, especially in the dermo-epidermal region.12 In addition, the fibers are reported to be distinctly "fuzzy" suggesting that the margins of the fibers are damaged.7,11 As is the case with collagen, alterations in elastin are seen in both intrinsic and actinic aging, although the actinic changes are more severe.13 It is thought that elastolysis plays an important role in not only the aging of skin, but also of the arteries, lungs, and other tissues.

Genetic perturbations in elastin biology are observed in cutis laxa, a family of metabolic defects in elastin maintenance. The syndrome is best known for the pronounced progeroid facies, with affected individuals looking many years older than their actual age, and the presence of aneurysms, emphysema, and other elastic disorders.14-17 It is believed that the disease has at least three genotypes, an autosomal dominant, an autosomal recessive, and an X-linked dominant form. While generally considered a defect in elastin synthesis or degradation,18 cells from the autosomal recessive form of the disorder have been reported to show a five-fold elevation in collagenase mRNA.19 This highlights what is probably a degree of overlap in elastin and collagen maintenance pathways.

Since the aging of skin is characterized by degenerative changes in the dermis, the next question we might ask is what accounts for the altered behavior of the cells that are responsible for maintaining the ECM. A cell generically referred to as the connective tissue fibro-blast is believed to have the primary responsibility of maintaining these proteins. We will now explore the regulation of fibroblast activity in conditions of stress, such as inflammation, wounding and aging.

Connective Tissue Maintenance

The above description of the ECM in aged tissues speaks more to the steady-state status than to the specific mechanisms of the degeneration. The mere existence of damaged ECM could be attributed to deficiencies in either the synthetic or proteolytic pathways or some combination of the two. Indeed the ECM is normally maintained through a continuous process of turnover with a temporally-regulated synthesis of structural proteins as well as proteolytic enzymes. Therefore, to find the cause of the altered status of the dermis during aging, one needs to consider the dynamic role of the fibroblast in maintaining the dermis.

In order to study the function of fibroblasts, and in particular, how that function may be altered in aging, an additional parameter must be considered. Fibroblasts respond in a dynamic fashion to a variety of extracellular signals such as platelet-derived growth factors

Fig. 14.1. Functional Dynamics of Young Fibroblasts. A.) Young proliferation—competent fibroblasts, may reside in a quiescent state characterized by a lack of cell division and by the secretion of proteins that maintain ECM. B.) In the presence of exogenous activators, for instance, those resulting from inflammation or wounding, the cells re-enter the cell cycle and up-regulate the production of proteins such as collagenase that transiently degrade the ECM to initiate tissue remodeling.

Fig. 14.1. Functional Dynamics of Young Fibroblasts. A.) Young proliferation—competent fibroblasts, may reside in a quiescent state characterized by a lack of cell division and by the secretion of proteins that maintain ECM. B.) In the presence of exogenous activators, for instance, those resulting from inflammation or wounding, the cells re-enter the cell cycle and up-regulate the production of proteins such as collagenase that transiently degrade the ECM to initiate tissue remodeling.

triggering a wound repair response, IL-1 an inflammatory response, IGF-1 a growth response, and so on. In the absence of such signals, the cells generally rarely divide and display a quiescent pattern of gene expression that facilitates the maintenance of the ECM. The fibroblast remodels the ECM through a clastic or destructive phenotype in which the cells destroy the extracellular proteins, and a blastic phenotype in which they synthesize new protein. A simplified characterization of this responsiveness is shown in Figure 14.1. The fibroblast in its normal maintenance state of "quiescence", proliferates at a low rate and produces relatively small quantities of proteolytic enzymes. In the presence of appropriate stimuli, the cells can re-enter the cell cycle, and increase the expression of proteolytic enzymes such as collagenase. This "activated" phenotype is typically a transient state such as postoperative day one in sutured incisions and day five of large defect full-thickness wounds and decreases back to quiescence thereafter.20

It is interesting to speculate why the up-regulation of genes like collagenase are nearly a universal characteristic of fibroblasts activated by a wide range of signals of tissue damage. Why would it be advantageous to degrade collagen in the case of a recent wound, or in the case of a local infection? One possibility is that many repair processes require the recruitment of accessory cells such as macrophages, to digest dead cells and tissues, cells that would normally be impeded in reaching the site in a rapid manner by the dense packing of the ECM components.

Matrix metalloproteinases (MMPs) play a critical role in the remodeling of connective tissues. Collagenase activity is the rate-limiting event in the degradation of collagen.21 This immortalization

weeks in vitro

weeks in vitro

Fig. 14.2. Replicative Senescence In Vitro. The curve shows the replicative history of a culture of mortal cells. Phase I, represents the cells growing from the original tissue explant, a period of active growth commences—termed phase II. After about 50-100 doublings, cell proliferation ceases in what is called phase III or Mortality-1 [M1]). In the presence of viral oncoproteins, such as SV40-Tantigen, Ml may be bypassed which allows the cell to proliferate up to 40% longer to a later horizon designated Mortality-2 (M2). Rare clones rising from populations of M2 cells may then "immortalize". That is, attain a capacity for indefinite growth (arrow).

initial proteolytic event allows it to "unwind" and it is subsequently degraded by gelatinases. Collagenase is believed to play an important role in such diverse degenerative disorders as; arthritis, gingivitis, and bone resorption.22 Other metalloproteinases such as stromelysins 1 and 2 target a broader array of proteins.23,24 These targets include: fibronectin, proteoglycan core protein, the nonhelical regions of elastin, collagen types II, IV, and IX, laminin, procollagens I and III, and gelatin. Collagenase and stromelysin must be activated from their proenzyme precursors by other proteases, one being plasminogen activator.25-27

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