The Biology of Aging Program (BAP) at the National Institute on Aging supports research in many areas, including processes of cell senescence and apoptosis, genetic influences on aging, and how aging leads to tissue dysfunction. Several approaches to research on aging physiological systems are described, along with BAP programmatic efforts to enhance and support that research. Understanding the relation between aging and tissue dysfunction has led to new insights into how health can be improved for aged individuals.

Membrane-bound endosomal vesicles play an integral role in multiple cellular events, including protein processing and turnover, and often critically regulate the cell-surface availability of receptors and other plasma membrane proteins in many different cell types. Neurons are no exception, being dependent on endosomal function for housekeeping and synaptic events. Growing evidence suggests a link between neuronal endosomal function and Alzheimer's disease (AD) pathophysiology. Endosomal abnormalities invariably occur within neurons in AD brains, and endocytic compartments are one likely site for the production of the pathogenic -amyloid peptide (A), which accumulates within the brain during the disease and is generated by proteolytic processing of the amyloid precursor protein (APP). The enzymes and events involved in APP processing are appealing targets for therapeutic agents aimed at slowing or reversing the pathogenesis of AD. The neuronal endosome may well prove to be the intracellular site of action for inhibitors of -amyloidogenic APP processing. We present here the view that knowledge of the endosomal system in the disease can guide drug discovery of AD therapeutic agents.

The European research project MiMage, supported by the European Community's Sixth Framework for Research and Technological Development, focuses on elucidating the role of mitochondria in conserved mechanisms of aging. This Perspective summarizes a selection of talks presented in April 2006 at the second MiMage symposium by members from participating laboratories and invited speakers.

Werner syndrome (WS) is a segmental progeroid syndrome in which patients display pleiotropic features of aging seen in the normal population. The advent of positional cloning in the 1990s markedly accelerated the identification of human disease-causing genes. In 1996, mutations in WRN, which was shown to encode a new, putative member of the family of RecQ DNA helicases, were identified in four patients as the cause of WS. Ten years after the identification of WRN, what have we learned about its role in WS, and its contribution to normal aging?

Metabolic syndrome refers to a constellation of risk factors for cardiovascular disease. They include elevated plasma glucose concentrations, dyslipidemia, hypertension, and abdominal obesity. These conditions typically occur during middle age or later in life. Although there is no clear consensus on the diagnosis of metabolic syndrome, it is a potentially important entity to recognize and manage once traditional cardiovascular risk factors, such as smoking, hypertension, dyslipidemia, and diabetes, have been treated individually. This Perspective summarizes our current knowledge of the metabolic syndrome. Lifestyle change, including diet and exercise, is probably the best available option for treating the metabolic syndrome. However, rigorous lifestyle interventions are difficult to implement outside of a clinical trial setting, especially among elderly patients.

In this case study, we review the symptoms, cognitive testing, brain imaging, and brain pathology of a woman with dementia, for whom the neuropathological findings suggest a prominent contribution of cerebrovascular disease. Vascular dementia is the term commonly used for persons with dementia resulting from strokes, either clinically evident or subclinical "silent" events. "Mixed dementia" is the term used when there is an admixture of pathological findings related to Alzheimer's disease (AD) and cerebrovascular disease, as in this situation. In some cases of mixed dementia, the pathological involvement of AD may be the principal contributory cause of the cognitive symptoms, and in others, the vascular changes may give the greater contribution.

The biggest risk factor for cancer isn't smoking or bad diet or anything a person can avoid. It's growing old. New findings might help explain the connection between aging and cancer. According to the study, a gene that's faulty in a disorder that resembles accelerated aging shuts down in many cancers.

What's left to learn about aging? The burning question for many researchers is whether life-stretching pathways and genes from model organisms boost human life span. Researchers might be able to track down additional genes and pathways that adjust longevity by studying a broader range of organisms or by tracking the evolution of genes that promote aging. An alternative way to extend our lives might be to identify the genes behind late-life killers such as heart disease and diabetes. Lab animals last longer on a very low-cal diet, and scientists are probing whether humans can benefit from this austerity. Or better yet, perhaps researchers can design molecules that deliver the gain of calorie reduction without the pain. Scientists are also focusing on which parts of the cell incur damage as we age and how growth and reproduction tie in to longevity. The speed of the next round of advances will depend on whether movers and shakers in funding organizations recognize the importance of the research and are willing to pay for it.

This article serves as a eulogy for the Science of Aging Knowledge Environment (SAGE KE). This online resource--Science's Web site on aging--is publishing its last issue today. The piece is a personal recollection of co-creating the site--and includes some thoughts on how the field of aging has changed over the last six years.