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It has long been known that aging, at both the cellular and organismal levels, contributes to the development and progression of the pathology of many chronic diseases. However, much less research has examined the inverse relationship-the contribution of chronic diseases and their treatments to the progression of aging-related phenotypes. Here, we discuss the impact of three chronic diseases (cancer, HIV/AIDS, and diabetes) and their treatments on aging, putative mechanisms by which these effects are mediated, and the open questions and future research directions required to understand the relationships between these diseases and aging.

The ATM (ataxia telangiectasia mutated) protein plays a central role in sensing and responding to DNA double-strand breaks. Lymphoid cells are unique in undergoing physiologic double-strand breaks in the processes of Ig class switch recombination and T or B cell receptor V(D)J recombination, and a role for ATM in these processes has been suggested by clinical observations in ataxia telangiectasia patients as well as in engineered mice with mutations in the Atm gene. We demonstrate here a defect in thymocyte maturation in ATM-deficient mice that is associated with decreased efficiency in V-J rearrangement of the endogenous T cell receptor (TCR)[alpha] locus, accompanied by increased frequency of unresolved TCR J[alpha] coding end breaks. We also demonstrate that a functionally rearranged TCR[alpha][beta] transgene is sufficient to restore thymocyte maturation, whereas increased thymocyte survival by bcl-2 cannot improve TCR[alpha] recombination and T cell development. These data indicate a direct role for ATM in TCR gene recombination in vivo that is critical for surface TCR expression in CD[4.sup.+]CD[8.sup.+] cells and for efficient thymocyte selection. We propose a unified model for the two major clinical characteristics of ATM deficiency, defective T cell maturation and increased genomic instability, frequently affecting the TCR[alpha] locus. In the absence of ATM, delayed TCR[alpha] coding joint formation results both in a reduction of [alpha][beta] TCR-expressing immature cells, leading to inefficient thymocyte selection, and in accumulation of unstable open chromosomal DNA breaks, predisposing to TCR[alpha] locus-associated chromosomal abnormalities. ataxia telangiectasia mutated | recombination | T cell development

Author(s): Richard J Hodes (corresponding author) [1] Some 4.5 million Americans currently suffer from Alzheimer disease. Scientists estimate that as the population continues to age and baby boomers reach retirement [...]

In vivo expression of human telomerase is significantly different from that of mouse telomerase. To assess the basis for this difference, a bacterial artificial chromosome clone containing the entire hTERT (human telomerase reverse transcriptase) gene was introduced in mice. In these transgenic mice, expression of the hTERT transgene was similar to that of endogenous hTERT in humans, rather than endogenous mTERT (mouse telomerase reverse transcriptase). In tissues and cells showing a striking difference in expression levels between hTERT in humans and mTERT in mice (i.e., liver, kidney, lung, uterus, and fibroblasts), expression of the hTERT transgene in transgenic mice was repressed, mimicking hTERT in humans. The transcriptional activity of the hTERT promoter was much lower than that of the mTERT promoter in mouse embryonic fibroblasts or human fibroblasts. Mutational analysis of the hTERT and mTERT promoters revealed that a nonconserved GC-box within the hTERT promoter was responsible for the human-specific repression. These results reveal that a difference in cisregulation of transcription, rather than transacting transcription factors, is critical to species differences in tissue-specific TERT expression. Our data also suggest that the GC-box-mediated, human-specific mechanism for TERT repression is impaired in human cancers. This study represents a detailed characterization of the functional difference in a gene promoter of mice versus humans and provides not only important insight into species-specific regulation of telomerase and telomeres but also an experimental basis for generating mice humanized for telomerase enzyme and its pattern of expression.

The future of aging therapies, specifically those that contribute to disease or dysfunction, is discussed. The study highlights the existence of needs and opportunities for novel molecular and cellular research strategies.