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4.5 - 29th November 1998


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The role of cellular senescence in skin aging.

Campisi J

Life Sciences Division, Berkeley National Laboratory, California 94720, USA.

J Investig Dermatol Symp Proc 1998 Aug;3(1):1-5

Higher organisms contain two types of cells: postmitotic cells, which never divide, and mitotic (or mitotically competent) cells, which can divide. Postmitotic cells include mature nerve, muscle, and fat cells, some of which persist for life. Mitotic cells include epithelial and stromal cells of organs such as the skin. Because postmitotic and mitotic cells differ in their proliferative capacity, they may age by different mechanisms. Normal somatic mitotically competent cells do not divide indefinitely. The process that limits the cell division number is termed cellular or replicative senescence. Replicative senescence is thought to be a powerful, albeit imperfect, tumor suppressive mechanism. It is also thought to contribute to organismic aging. Senescent cells undergo three phenotypic changes: they irreversibly arrest growth, they acquire resistance to apoptotic death, and they acquire altered differentiated functions. The growth arrest is very likely critical for the role of replicative senescence in tumor suppression, but may be less important for the aging of organs such as the skin. On the other hand, the altered differentiation may be critical for compromising the function and integrity of organs like the skin during aging. Senescent keratinocytes and fibroblasts appear to accumulate with age in human skin. Moreover, senescent cells express genes that have long-range, pleiotropic effects - degradative enzymes, growth factors, and inflammatory cytokines. Thus, relatively few senescent cells might compromise skin function and integrity. Moreover, by altering the tissue microenvironment, senescent cells may also contribute to the rise in cancer that occurs with age.


The evolution of aging: a new approach to an old problem of

biology.

Bowles JT

Med Hypotheses 1998 Sep;51(3):179-221

Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development. The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population turnover, which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging systems (ASs). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective defenses to predation that allow exceptionally long lifespans to evolve are shells, extreme intelligence, isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging systems. Aging organisms should have one dominant, aging system that co-opts vestiges of earlier-evolved systems as well as vestiges of prior systems. In human evolution, aging systems chronologically emerged as follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression (AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy (AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible aging systems. The life-extending/rejuvenating effects of caloric restriction support the idea of aging reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome. Methylated cytosines (5mC) inhibit gene transcription, and deoxyribonucleic acid (DNA) cleavage by restriction enzymes. Cleavage inhibition prevents apoptosis, which requires DNA fragmentation. Free radicals catalyze the demethylation of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA methyltransferases. Hormones act as either surrogate free radicals by stimulating the cyclic adenosine monophosphate (cAMP) pathway or as surrogate antioxidants through cyclic guanosine monophosphate (cGMP) pathway stimulation. Access to DNA containing 5mC inhibited developmental and aging genes and restriction sites is allowed by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase generates free radicals during strand separation; hormones either amplify or counteract this effect. Caloric restriction slows or reverses the aging process by increasing melatonin levels, which suppresses reproductive and free radical hormones, while increasing antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA, which increases bioavailable cGMP. The rapid aging diseases of progeria, the three diseases: (xeroderma pigmentosum (XP), Cockayne syndrome(CS), and ataxia telangiectasia (AT)), and Werner's syndrome are related to or caused by defects in three separate DNA helicases. The rapid aging diseases caused by mitochondrial malfunctions mirror those seen in XP, CS, and AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective aging systems. Follicle-stimulating hormone (FSH) demethylates the genes of AS#4, luteinizing hormone (LH) of AS#5, and estrogen of AS#6 while cortisol may act cooperatively with FSH and LH, and 5-alpha dihydrotestosterone (DHT) with FSH in these role. The Werner's DNA helicase links timing of the age of puberty, menopause, and maximum lifespan in one mechanism. Telomerase is under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of AS#5 and AS#6.


The two-process model of cellular aging.

Kitano H, Imat S

Sony Computer Science Laboratory, Tokyo, Japan. kitano@csl.sony.co.jp

Exp Gerontol 1998 Aug;33(5):393-419

To understand the mechanism of aging at the cellular level, cellular senescence has been extensively studied as an experimental model of aging in vitro. Although several hypotheses have been proposed for the mechanism of cellular senescence, none of them could give a comprehensive framework to the mechanism. In this study, we showed our results of extensive computer simulation designed to identify possible molecular models of cellular senescence. By examining representative cases of various molecular models, we elucidated the requirements for the plausible mechanism of cellular senescence. Based on these simulation results, we proposed a new molecular model of cellular senescence--the two-process model. In this model, we assumed that two independent, but time-aligned regulatory processes functioned in individual cells. We defined these two processes as S- and C-processes. The S-process mainly determines the rate of decline in the proliferative potential of the cell population. The simulation results suggested that the growth-inhibitory cell-to-cell interaction was required to drive the S-process. The C-process determines the latent proliferative potential of individual cells. The effector genes for the C-process are suggested to be regulated by a certain threshold-type mechanism. Both growth kinetics and senescence-associated gene expression were generated with high accuracy by the combined effect of these two processes. We also succeeded in simulating the effects of simian virus 40 large T antigen and its inducible variant on cellular senescence. From these theoretical considerations, we discuss the validity of the two-process model and the possible involvement of the heterochromatin structure as a determinant of the replicative lifespan of cells.

Aging in epidermal melanocytes: cell cycle genes and melanins.

Haddad MM, Xu W, Medrano EE

Huffington Center on Aging and Department of Cell Biology, Baylor College of Medicine and VAMC, Houston, Texas 77030, USA.

J Investig Dermatol Symp Proc 1998 Aug;3(1):36-40

With aging, melanocytes become unevenly distributed in the epidermis. In light skin individuals, hypopigmentation is found in association with focal hyperpigmentation (lentigo senilis). Apparently this results from progressive loss of active melanocytes and focal increase in melanocyte proliferation and/or aggregation. This paper summarizes the present knowledge on aging of melanocytes in vivo and in vitro, with a focus on the role of melanin as a determinant for proliferation and terminal differentiation. We describe that excessive melanin deposition by cyclic AMP-inducing agents results in increased expression of the cyclin-dependent kinase inhibitors p27Kp-1 and p21SDI-1/Waf-1, increased binding of p16 to CDK4, and terminal differentiation. Importantly, the efficiency with which the melanocytes exit the cell cycle depends on the melanin background of the donor's cells. Melanocytes from skin types IV-VI that accumulate large amounts of brown black melanin (eumelanin), lose expression of the transcription factors E2F1 and E2F2, two key regulatory proteins, and withdraw from the cell cycle more rapidly than melanocytes from skin types I and II that accumulate red/yellow melanin (pheomelanin). Thus, we propose that terminal differentiation is a tumor suppressor mechanism that becomes less efficient under imperfect eumelanization.


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