Cellular proliferation potential during aging and caloric restriction in rhesus monkeys (Macaca mulatta)

Abstract

Caloric restriction (CR) is the most successful method of extending both median and maximal lifespans in rodents and other short-lived species. It is not yet clear whether this method of life extension will be successful in longer-lived species, possibly including humans; however, trials in rhesus monkeys are underway. We have examined the cellular proliferative potential of cells from CR and AL (ad libitum fed) monkey skin cells using two different bioassays: colony size analysis (CSA) of dermal fibroblasts isolated and cloned directly from the skin and beta-galactosidase staining at pH 6.0 (BG-6.0) of epidermal cells in frozen sections of skin. Decreases in both proliferative markers occurred with age, but no differences were observed between CR and AL animals. Skin biopsies were obtained from AL and CR rhesus monkeys from two different aging colonies, one at the National Institute on Aging (NIA) and one at the University of Maryland-Baltimore (UMB). These biopsies were used as a source of tissue sections and cells for two biomarkers of aging assays. The CR monkeys had been maintained for 9-12 years on approximately 70% of the caloric intake of control AL animals. In the CSA studies, the fraction of small clones increased significantly and the fraction of large clones decreased significantly with increasing age in AL monkeys. The frequency of epidermal BG-6.0 staining cells increased with age in older (>22 years) AL monkeys, but most predominately in those of the UMB colony, which were somewhat heavier than the NIH AL controls. Old monkeys on CR tended to have fewer BG-6.0-positive cells relative to old AL-derived epidermis, but this effect was not significant. These results indicate that cellular proliferative potential declined with age in Macaca mulatta, but was not significantly altered by CR under these conditions. Although these experiments are consistent with an absence of effect of CR on monkey skin cell proliferative potential, we have found in previous experiments with mice that a longer duration of CR (as a fraction of total lifespan) was needed to demonstrate CR-related improvement in clone size in mice. Further studies on the now mid-aged monkeys will be needed as their age exceeds 20 years to conclusively rule out an effect of CR on proliferative potential of skin cells from these primates.

Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging

“…We speculate that the growth arrest was selected to ensure that damaged, mutant, or inappropriately stimulated cells-cells at risk for neoplastic transformation-do not proliferate. By contrast, the functional changes may be unselected consequences of the growth arrest, having little impact on young organisms where senescent cells are rare (8)(9)(10). However, as damage, telomere attrition, or errors cause senescent cells to accumulate with age, their influence, particularly their secretory phenotype, may become significant and deleterious.…”

“…In addition to arresting growth, senescent cells show changes in function (2,6,7). Because senescent cells accumulate with age (8)(9)(10), they may contribute to age-related declines in tissue function. If so, cellular senescence may be an example of antagonistic pleiotropy.…”

Aging, tumor suppression and cancer: high wire-act!

“…Indeed, such (SABgal-positive) cells have been found in several tissues from humans and rodents. More important, their frequency has been shown to rise with increasing age in human skin, monkey skin and retina, human prostate, rodent kidney, human liver and human vascular endothelium (Dimri et al, 1995;Mishima et al, 1999;Pendergrass et al, 1999;Choi et al, 2000;Ding et al, 2001;Paradis et al, 2001;Vasile et al, 2001;Melk et al, 2003). Moreover, as discussed below, cells with senescent characteristics have been found at sites of age-related pathology, including atherosclerotic plaques and benign and premalignant lesions of the liver and prostate.…”

Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes

“…Upon senescence, at least some cell types become resistant to certain apoptotic signals (Wang et al, 1994;Linskens et al, 1995;Seluanov et al, 2001). This resistance to apoptosis may explain why senescent cells can accumulate in tissues with age (Dimri et al, 1995;Pendergrass et al, 1999;Choi et al, 2000;Ding et al, 2001;Paradis et al, 2001). Equally important, senescent cells tend to overexpress secreted molecules, which can act at a distance within tissues and disrupt the local microenvironment.…”

“…As dysfunctional senescent cells accumulate in vivo (Dimri et al, 1995;Pendergrass et al, 1999;Choi et al, 2000;Ding et al, 2001;Paradis et al, 2001), their secretory phenotype might lead to disruption of the local tissue microenvironment. This disruption might explain the loss of tissue integrity and function that is a hallmark of aging (Campisi, 1997;Campisi, 2000).…”