Mechanisms of Aging

In the past decade, scientific research has made astounding progress in elucidating the mechanism of aging of the human body, including the integument.As one might expect, aging appears to be due to a composite of genetic as well as environmental factors. There appear to be several mechanisms and mediators that control the multiple components of the human aging process. For example, in several lower species, the genes controlling longevity have been successfully identified; corresponding genes are now being investigated in humans. Derangements in the genes that control premature aging syndromes have been identified and provide insight into the mechanism of aging.Chromosomal structures responsible for cell senescence are known to play a crucial role in both intrinsic and photoaging. Furthermore, the role of free radicals in the aging process has been long recognized. Finally, the likely molecular mechanism whereby UV light produces cellular damage leading to photoaging has been elucidated. Each of these components, as outlined below, will lead to a more complete understanding of the complex process of aging in humans.

Although a gene that controls the overall aging process has not been identified in humans, in organisms such as fungi, yeast, and fruit flies, 35 genes that determine life span have been cloned [4]. These genes are responsible for many different functions, suggesting that there are multiple mechanisms of aging. In the lower organisms studied, Jazwinski identified four principle processes responsible for aging, which include: metabolic control, resistance to stress, gene dysregulation, and genetic stability. Some of the longevity genes identified respond to stresses such as ultraviolet radiation, oxidative damage, starvation, and temperature extremes. There are conceivably many ways to impact these genetic processes and improve longevity, such as caloric restriction, which may potentially affect metabolic control and stress. Many human homologs of the longevity genes found in lower organisms have been identified and are currently being studied [5]. It is proposed that manipulation of these genes might improve human longevity.

The fact that genes play a crucial role in aging is supported by genetic disorders in which the aging process is greatly altered, such as in Werner’s syndrome.Werner’s syndrome, a disorder of premature aging, is characterized by many features, including an aged appearance, premature canities, alopecia, skin atrophy, cataracts, arteriosclerosis, and death before age 50. Evaluation of individuals with this syndrome has provided insight into one possible genetic mechanism of aging. The Werner’s syndrome gene, which was cloned by Yu, has been identified as a DNA helicase [6]. Defective DNA metabolism as a result of the Werner’s syndrome mutation is felt to be responsible for premature aging in these individuals. In progeria, another genetic disorder of accelerated aging, a misregulation of mitosis has been identified as the mechanism of premature aging [7]. An analysis of fibroblast mRNA levels in progeria patients revealed misregulation of structural, signaling, and metabolic genes. Thus, several different genes may be responsible for various aspects of aging.


Much attention has been given to genetically programmed cell death as the final common pathway to aging. Cellular senescence, the inability of cells to divide indefinitely (cell death), occurs as a result of intrinsic aging as well as photoaging. Cell senescence is controlled by telomeres. Telomeres are the repeating DNA base sequences thymine-thymine-adenineguanine- guanine-guanine (TTAGGG) at the ends of chromosomes [8]. They are thousands of base pairs long and protect the ends of each chromosome from damage. Shortening of the telomere has been demonstrated in older adults, compared with younger individuals, and in individuals with premature aging as in Werner’s syndrome, thus supporting the importance of telomeres in aging [9, 10]. With each round of cell division, telomeres become shorter and shorter until a point is reached when the cell is no longer able to divide and cell death occurs. There is a folded structure at the very end of the telomere that consists of an array of 150–200 single-stranded bases referred to as the 3′ overhang [11]. The 3′ overhang is configured in a folded loop that serves a protective function [12]. As the chromosome replicates, a critical point is reached when the overhang is exposed and digested [13]. Cell signaling occurs (by the ataxia telangiectasia mutated kinase protein and the p53 tumor suppressor protein) causing senescence of cells, such as fibroblasts and apoptosis of lymphocytes [14]. In addition to repeated replication, as occurs in intrinsic aging producing telomere shortening and disruption, acute DNA damage as occurs in photoaging also leads to activation of the same mediators, telomere shortening, and cell senescence. Acceleration of aging occurs with UV damage that, in addition to shortening and disrupting telomeres, causes increased cell division to repair DNA thus leading to even further shortening of telomeres. Telomerase, a ribonucleoprotein identified in tumor cells makes telomeric sequences to replace shortened telomeres [15]. Bodnar demonstrated an extension of life span by the introduction of telomerase into retinal epithelial cells and fibroblasts [16]. In an experimental model utilizing DNA oligonucleotides, which mimic the telomere 3’ overhang, Gilchrest’s group demonstrated that treatment with oligonucleotides may mimic telomere disruption signals without affecting the cell’s own DNA and thus enhance the DNA repair process [17].

Although the free radical theory of aging has received much attention recently with the increasing popularity and commercialization of antioxidant products, it is a theory that dates back over 40 years [18]. The theory is that aging is caused by free radicals or reactive oxygen species, which are molecules with an unpaired electron. Free radicals that include singlet oxygen (¹O₂), superoxide (O₂^-), hydrogen peroxide (H₂O₂), and hydroxyl radical (HO) strongly attract electrons from DNA, cell membranes, and proteins, which leads to damage of those components. The damage done by free radicals contributes to aging. Both intrinsic and extrinsic aging generate free radicals through either internal oxidative metabolism or through external environmental factors, including pollution, cigarette smoking, and UV radiation [19]. A common pathway involving telomeres links free radicals to aging. Free radicals target the guanine residues that make up 50% of the telomere overhang structure [20].

The likely molecular mechanism explaining photoaging was elucidated by Fisher [21]. The basic tenant is that in photoaging, UV light generates free HOs, which stimulate matrix metalloproteinases (MMP) that then degrade extracellular matrix components. More specifically, cell surface receptors, including epidermal growth factor receptor and cytokine receptor, on keratinocytes and fibroblasts are activated by UV light. Three mitogen-activated protein kinase (MAP) pathways are then activated: extracellular signal-regulated kinase (ERK), cJun amino-terminal kinase (JNK), and p38. These pathways converge in the cell nucleus, and two transcription factor components, cFos and cJun, combine to form activator complex 1 (AP- 1). AP-1 then simulates the transcription of MMP genes to produce collagenase, 92-kd gelatinase, and stromelysin-1. These enzymes degrade collagen, elastin, and other extracellular matrix components. With repeated UV exposure, more dermal damage occurs that cannot be fully repaired, leading over time to photoaged skin.

In his elegant series of experiments, Fisher irradiated white skin with UV lights and then evaluated it by a variety of techniques [21]. A single exposure to UV irradiation increased the expression of the three MMPs previously discussed compared with nonirradiated skin, which did not. Degradation of type I collagen fibrils was increased by 58% in the irradiated skin compared with nonirradiated skin. UV irradiation also induced tissue inhibitor of matrix metalloproteinases-1, which partially inhibited MMPs. Of note, pretreatment of skin with tretinoin inhibited the induction and activity of MMPs by 70–80% in connective tissue as well as the outer layers of irradiated skin. Kang recently demonstrated that the generation of free radicals by UV light was impaired by the antioxidant genistein and the antioxidant precursors n-acetyl cysteine [22].