Altered controls of proliferation in proximal small intestine of the senescent rat.

Holt, Peter R.; Yeh, Kwo–Yih; Kotler, Donald P.

doi:10.1073/pnas.85.8.2771

Cited by 67 publications

(24 citation statements)

References 18 publications

(17 reference statements)

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“…In other words, not only are there differences between species, but there are differences between tissues in their response to the dyotic signaling. For instance, in humans, while skin cells (fibroblasts) do display decreased cellular proliferation during senescence [Dimri et al, 1995], cell types such as colonic and prostatic cells display increased proliferation during senescence [Hermann and Berger, 1999;Holt et al, 1988;Saxena et al, 1995]. The different responses to the serum dyotic signal are due to tissuespecific hormone receptor expression patterns.…”

Section: Senescencementioning

confidence: 99%

Living and Dying for Sex

2004

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A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms. The theory also puts forth a new definition of aging – any change in an organism over time. This definition includes not only the changes associated with the loss of function (i.e. senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development). Using this definition, the rate of aging would be synonymous with the rate of change. The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth. Therefore, ‘fetal aging’ would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death. We suggest that these factors also are responsible for regulating aging throughout life. Thus, whatever controls mitogenesis, differentiation and cell death must also control aging. Since life-extending modalities consistently affect reproduction, and reproductive hormones are known to regulate mitogenesis and differentiation, we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging). In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones. Longevity inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/Akt/Forkhead pathway. This is exemplified by genetic alterations in Caenorhabditis elegans where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events. In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence.

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Section: Senescencementioning

confidence: 99%

Living and Dying for Sex

2004

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“…However, careful evaluation of jejunal biopsy specimens from healthy elderly volunteers shows that the anatomy of epithelial cells and the surface area does not differ from that found in the young [1] . In the rat, although villus cell numbers in the proximal small intestine are similar in the young and old, crypt cell numbers are greater in Fischer 344 rats over age 24 months [2] accompanied by increased epithelial cell proliferation [3] and altered controls of cell production [4] . Similar changes have been described in the human small bowel epithelium [5] .…”

Section: Structural and Functional Changes In The Small Intestinementioning

confidence: 99%

Intestinal Malabsorption in the Elderly

Holt¹

2007

Dig Dis

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Background: Intestinal malabsorption in the elderly is infrequent, and clinical features are muted so that the diagnosis is often missed. Physiologic changes with aging are restricted to altered absorption of calcium and perhaps zinc and magnesium; however, achlorhydria can lead to impaired absorption of vitamin B₁₂, folic acid, and calcium. Methods and Results: Small bowel bacterial overgrowth occurs more commonly in elderly than in younger patients, accompanying gastric hypochlorhydria, altered intestinal motor activity, or diseases such as Parkinson’s disease. Changes in pancreatic anatomy and secretion occur but are insufficient to produce macronutrient malabsorption. In addition to pancreatic cancer and pancreatic stones, older patients may present with severe pancreatic insufficiency of unknown etiology. Celiac disease is recognized as very common at all ages and may not become evident until late in life. Manifestations of celiac disease in the elderly are occult and the diagnosis often is not considered until serologic tests are performed and confirmed by upper small intestinal biopsy. Associated intestinal lymphoma, esophageal carcinoma, intestinal pseudo-obstruction, and splenic atrophy may be more common in the elderly. Treatment of older patients with celiac disease with a gluten-free diet may be difficult, and intensive vitamin and micronutrient replacement is mandatory. A pragmatic approach to the evaluation of malabsorption in elderly patients is discussed.

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“…Biochemical reactions could alter the metabolism of puta Dig Dis I997;I5:302-311tive carcinogens, change rates of epithelial cell proliferation or apoptosis, and alter absorp tion rates that might influence colonocyte concentrations of bioactive compounds. The replicative potential and rate of a tissue is believed to be an important factor that con tributes to carcinogenesis [20], In the rat, epi thelial cell proliferation is faster in the distal than in the proximal colon [21], A gradient for the concentration of ornithine decarboxylase, the rate-limiting enzyme of polyamine syn thesis, increases as one proceeds from proxi mal to distal colon [22]. Elevated ornithine decarboxylase levels are associated with hy perproliferation in the colonic mucosa [23].…”

Section: Biochemical Changesmentioning

confidence: 99%

Are Right- and Left-Sided Colon Neoplasms Distinct Tumors?

Distler

Holt²

1997

Dig Dis

116

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Cancer of left and right colon has a differing prevalence at varying ages, in high- and low-incidence nations, as well as in men and in women. There also is a difference in clinical presentation, in prognosis, and possibly in genetic and environmental epidemiology. This review proposes that cancers of proximal and distal colon are different tumors because of their embryologic origin, genetic changes, and biologic identity. These factors are important in understanding the ‘shift of tumors from more distal to more proximal sites in the colon’ and in evaluating potential suggestions for instituting advances in diagnosis and prevention.

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Altered controls of proliferation in proximal small intestine of the senescent rat.

Cited by 67 publications

References 18 publications

Living and Dying for Sex

Living and Dying for Sex

Intestinal Malabsorption in the Elderly

Are Right- and Left-Sided Colon Neoplasms Distinct Tumors?

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