Centenarians represent an extreme of life expectancy. They achieve their exceptional longevity in part by lacking genetic variations linked to premature death. Pedigree studies have shown a substantial familial component in the ability to survive to extreme old age, and a recent study demonstrated a locus on chromosome 4 linked to exceptional longevity, indicating the likely existence of at least one longevity-enabling gene in humans. The children of centenarians have markedly reduced relative risks for age-related diseases, particularly heart disease, hypertension, and diabetes, and are a promising model for genetic and phenotypic studies of 1) aging slowly relative to the general population and 2) the delay of and perhaps escape from important age-related diseases. These studies and those of other mammals and lower organisms show great promise for the delineation of important environmental and genetic determinants of aging well.

While there are many examples of people who live for 100 years or more with little evidence of a decline in brain function, many others are not so fortunate and experience a neurodegenerative disorder, such as Alzheimer disease or Parkinson disease. Although an increasing number of genetic factors that may affect the risk for neurodegenerative disorders are being identified, emerging findings suggest that dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disorder. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons. Epidemiologic findings suggest that high-calorie diets and folic acid deficiency increase the risk for Alzheimer disease and Parkinson disease; studies of animal models of these disorders have shown that dietary restriction (reduced calorie intake or intermittent fasting) and dietary supplementation with folic acid can reduce neuronal damage and improve behavioral outcome. Animal studies have shown that the beneficial effects of dietary restriction on the brain result in part from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although additional studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to age-related neurodegenerative disorders, particularly in persons with a genetic predisposition to such disorders.

Genetic epidemiology has greatly expanded its scope as a result of major technological innovations in the past decade. Laboratory capacity to determine DNA variation and archival information on the human genome sequence are now readily available. A wide range of research projects have been launched on chronic disease and health problems of aging, on the assumption that a better understanding of mechanisms will improve treatment and prevention. In many instances, the actions of genes are known to be modified by environmental conditions, and considerable emphasis has now been placed on finding specific interactions between genes and the environment. Studies in agriculture and animals provide clear empirical evidence on the importance of this concept. Describing gene-environment interactions in studies of humans is still very challenging, however, given the difficulties in study design and measurement. Despite the theoretical value of characterizing both intrinsic and extrinsic components of the causal process in the development of disease, the argument can also be made that main effects of each component separately are much more important. For these reasons, gene-environment interactions are likely to remain a conceptual framework for health research rather than a practical goal for the foreseeable future.

The high burden of illness and frailty common among our growing population of older adults often results in fragmentation of care across providers and health care systems, increasing the complexity and costs of caring for these patients. Information technology offers one way to meet this challenge. Scientists at the Regenstrief Institute have more than a quarter-century of experience in using medical informatics to support clinicians in the day-to-day care of older adults. Their research has progressed through several evolutionary cycles, beginning with the acquisition of relevant data and moving to studies of the most efficient and effective mechanisms that bring information to bear at the time of clinical decision making. Information technology designed with the input of the end user has the greatest promise of changing provider behavior because it balances technological challenges with the cultural context of the practice environment. One topic of active research is information technology to support transitions of care among sites and providers. These transitions place older adults at increased risk for avoidable illness, death, and health care costs. Information systems that improve communication among providers during these transitions have the potential to improve safety and reduce costs.

Effective health care is a core determinant of successful aging, and medications are one of the most important therapeutic tools of health care providers. Most older adults use at least one prescription drug. Costs for these drugs are a substantial out-of-pocket expense for Medicare beneficiaries, and low-income older adults must weigh these costs against those of other basic needs. Although medications bring welcome relief to millions of elderly persons with age-related conditions, adverse drug events are an important cause of illness and death in these patients. Thus, the appropriate, cost-effective use of medication is central to successful aging. Despite increasing attention to geriatric pharmacotherapy, there is an enormous need for additional research to improve the use of medications among older adults. The necessary research agenda encompasses much more than just the discovery of new drugs; better use of the current pharmacopeia has great potential to improve the lives of older adults. We review four domains of pharmaceutical research: drug discovery and delivery, drug efficacy and safety, pharmacoepidemiology and drug policy, and improved access to and use of drugs. These domains encompass both the pre- and postmarketing phases of drug research. Premarketing research currently has greater magnitude and a better infrastructure than postmarketing research, yet issues arising in the two phases of research are equally important to the health and safety of older adults. A national, federally supported pharmaceutical database could greatly enhance the infrastructure of postmarketing research. However, many major improvements in medication use among older adults will also depend on closing the gap between knowledge and practice and increasing the ability of older adults to manage their medications.

Health care of the highest quality promotes successful aging. This paper examines the efforts that have been taken to improve the quality of health care, especially hospital care. Most of these efforts have evaluated conventional treatments of specific diseases; they are critical but underfunded and underused, and many practices persist without much evidence of efficacy. Fewer efforts have attempted to improve care for groups of persons in specific settings, such as the hospital. Three complementary approaches to improving comprehensive outcomes for hospitalized older persons-Geriatric Evaluation and Management, Acute Care for Elders, and the Elder Life Program-demonstrate what has been learned about improving care for older persons by redesigning microsystems of care. A research agenda for advancing successful aging should include specific actions to improve the quality of health care.

Improving end-of-life experience is a major challenge to successful aging. Deaths that are reasonably free of discomfort, in accordance with patients' wishes, and within acceptable professional and ethical standards are high-quality deaths. The authors developed a 31-item measure of the quality of dying and death and applied it in a community sample and a sample of hospice enrollees. Scores on the Quality of Dying and Death Instrument and measures of perceived quality of care were collected from patients' loved ones after death. Higher overall after-death ratings of the quality of care received from all providers and from physicians were associated with higher-quality dying and death. How well patients' symptoms were controlled in the community study and how well wishes were followed and treatments were explained in the hospice study were associated with higher-quality dying. Major challenges to end-of-life research include recruiting representative population samples, given widespread reluctance of patients and loved ones to participate in research at the end of life; important variation in evaluations among different reporters after death; reluctance of loved ones to assign negative evaluations to dying experiences after death; and the highly individual and dynamic nature of dying experiences. Overcoming these challenges is of great importance in the search for the social, organizational, and individual determinants of high-quality dying in the U.S. cultural and health care context.

The past 50 years have seen great progress in the measurement of patient-based outcomes for older populations. Most of the measures now used were created under the umbrella of a set of assumptions and procedures known as classical test theory. A recent alternative for health status assessment is item response theory. Item response theory is superior to classical test theory because it can eliminate test dependency and achieve more precise measurement through computerized adaptive testing. Computerized adaptive testing reduces test administration times and allows varied and precise estimates of ability. Several key challenges must be met before computerized adaptive testing becomes a productive reality. I discuss these challenges for the health assessment of older persons in the form of 10 "Ds": things we need to deliberate, debate, decide, and do.

Interventions designed to encourage people to change high-risk behavior have not been very successful. This is an important challenge because the number of older people in the population will double within the next 20 to 30 years. The increase will put enormous strain on an already overburdened medical care system. We therefore will need to put more emphasis on disease prevention programs. Helping people change high-risk behavior will be the key to prevention. To develop more effective prevention programs, we will have to train a new generation of experts who can not only provide people with risk information but also work with them as partners in achieving mutually agreed upon goals.

Social capital is defined as the resources available to individuals and groups through social connections and social relations with others. Access to social capital enables older citizens to maintain productive, independent, and fulfilling lives. As the U.S. population ages, accompanied by a rise in the prevalence of seniors living alone, the availability of social capital within communities will become an important ingredient of successful aging. Recent evidence suggests that many traditional forms of social capital in communities-as represented by civic engagement in local associations and by the extent of voluntarism and social trust-are on the decline. If this observation in correct, there is no simple solution to rebuilding this lost social capital. Novel forms of senior housing, such as planned care developments and assisted-living facilities, may offer promising modes of delivery of social capital to the aging population. However, assisted living remains financially inaccessible for a large segment of the U.S. population, so investment in communities "aging in place" may be the key to delivering the health dividends of social capital.

Successful aging is defined not by longevity alone but also by sufficient well-being (in multiple domains) to sustain a capacity for functioning adequately in changing circumstances. The determinants of such well-being and functional status are manifold and include the genetic endowment, physical environment, social environment, population and individual responses to challenges, the occurrence of disease, availability and effectiveness of health care, and personal prosperity. In the face of such complexity, scientific approaches to the phenomena associated with successful aging should be appreciative and wholistic as well as reductionistic. Such a "natural science" of aging will be required to uncover and use information about linear, cause-and-effect phenomena, as well as about higher-order emergent patterns that are of relevance to the health of elderly persons, such as "resilience" and "generativity." Taken as a whole, this multimethod research agenda will truly express an integrated biopsychosocial approach to research on successful aging.

Families of internationally adopted children face risks associated with travel if they pick up their children overseas. Unlike other travelers, they also face risks because of close contact with a child with uncertain infection and vaccination status. Tuberculosis organisms, hepatitis A virus, hepatitis B virus, and measles virus have been transmitted from adopted children to family and community members. Intestinal parasites, Bordetella pertussis, and other infectious disease agents can also be transmitted. Some of these infections may be inapparent or may not manifest in adopted children until many years after the adoption. Increased attention to preventive measures for family members and early diagnosis of infectious diseases in adopted children can reduce transmission of the organisms causing these infections. Those providing health care to families planning international adoption should know about standard pretravel advice, as well as the spectrum of possible infections in adopted children, so that they can protect the health of the travelers and family members and close friends who will welcome the new child into the home.

HIV infection is associated with several renal syndromes, including acute renal failure. Chronic renal failure directly linked to HIV infection includes thrombotic microangiopathic renal diseases, immune-mediated glomerulonephritides, and HIV-associated nephropathy. A renal biopsy may be necessary for diagnosis. The development of HIV-associated nephropathy has been definitively linked to renal cellular infection, but the disease affects only a minority of patients, typically men of African descent. Therefore, factors determining disease expression in infected patients must now be emphasized. The pathogenic mechanisms involved in HIV-associated renal disease remain obscure. Genetic factors, as well as renal cellular responses, mediated by HIV proteins (including an immune-activated microenvironment) capable of presenting antigen in susceptible hosts probably explain most cases. HIV-associated nephropathy has a characteristic pathologic phenotype, including glomerular, tubular, and interstitial changes, and ultrastructural findings. Infection of the glomerular epithelial cell, or podocyte, and consequent structural and biochemical changes may be pivotal in pathogenesis. The HIV-1 transgenic mouse is an important model for understanding disease pathogenesis, particularly the role of HIV proteins in mediating renal tissue injury. Rigorously controlled randomized trials have not evaluated treatment, but corticosteroids and angiotensin-converting enzyme inhibitors have been used. Highly active antiretroviral therapy seems to have decreased the incidence of end-stage renal disease related to HIV infection and, in case reports, to have improved renal functional and pathologic outcomes of HIV-associated nephropathy. Outcomes in patients undergoing hemodialysis and peritoneal dialysis have improved, and current research focuses on renal transplantation for treatment of HIV-infected patients.

The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency.

Chronic kidney disease is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. Outcomes of chronic kidney disease include not only kidney failure but also complications of decreased kidney function and cardiovascular disease. Current evidence suggests that some of these adverse outcomes can be prevented or delayed by early detection and treatment. Unfortunately, chronic kidney disease is underdiagnosed and undertreated, in part as a result of lack of agreement on a definition and classification of its stages of progression. Recent clinical practice guidelines by the National Kidney Foundation 1) define chronic kidney disease and classify its stages, regardless of underlying cause, 2) evaluate laboratory measurements for the clinical assessment of kidney disease, 3) associate the level of kidney function with complications of chronic kidney disease, and 4) stratify the risk for loss of kidney function and development of cardiovascular disease. The guidelines were developed by using an approach based on the procedure outlined by the Agency for Healthcare Research and Quality. This paper presents the definition and five-stage classification system of chronic kidney disease and summarizes the major recommendations on early detection in adults. Recommendations include identifying persons at increased risk (those with diabetes, those with hypertension, those with a family history of chronic kidney disease, those older than 60 years of age, or those with U.S. racial or ethnic minority status), detecting kidney damage by measuring the albumin-creatinine ratio in untimed ("spot") urine specimens, and estimating the glomerular filtration rate from serum creatinine measurements by using prediction equations. Because of the high prevalence of early stages of chronic kidney disease in the general population (approximately 11% of adults), this information is particularly important for general internists and specialists.

While performance of percutaneous coronary intervention (PCI) remains the domain of specialized cardiologists, patients undergoing PCI are cared for by noninvasive cardiologists, internists, and primary care physicians. Therefore, patient care is optimized when the entire patient care team understands procedural risks and complications as well as optimum patient management before, during, and after PCI. Before PCI, patients with contrast dye allergies should be identified and pretreated with steroids and an H1-blocker. Hydration should be initiated and maintained before and after the procedure to minimize the risks for contrast nephropathy. Periprocedure, patients should be monitored clinically for evidence of ischemia. In patients with significant groin, flank, abdominal, or back pain, as well as those with decrease in hematocrit or unexplained hypotension, the diagnosis of groin or retroperitoneal hematoma should be considered and promptly evaluated. Groin tenderness, pulsatile mass, or bruit should prompt evaluation for possible femoral pseudoaneurysm or arteriovenous fistulae. After the procedure, all patients treated with coronary stents should receive aspirin plus clopidogrel. Patients who develop typical anginal symptoms between the 1st and 6th to 8th months after PCI are likely to have restenosis and can be evaluated by an imaging study or repeated catheterization.

Antioxidant vitamins are thought to play a role in atherosclerosis. Supplementation of these nutrients has been explored as a means of reducing cardiovascular morbidity and mortality.