Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity.

Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

A Unified Model of Age-Related Cardiovascular Disease.

Despite progress in biomedical technologies, cardiovascular disease remains the main cause of mortality. This is at least in part because current clinical interventions do not adequately take into account aging as a driver and are hence aimed at suboptimal targets. To achieve progress, consideration needs to be given to the role of cell aging in disease pathogenesis. We propose a model unifying the fundamental processes underlying most age-associated cardiovascular pathologies. According to this model, cell aging, leading to cell senescence, is responsible for tissue changes leading to age-related cardiovascular disease. This process, occurring due to telomerase inactivation and telomere attrition, affects all components of the cardiovascular system, including cardiomyocytes, vascular endothelial cells, smooth muscle cells, cardiac fibroblasts, and immune cells. The unified model offers insights into the relationship between upstream risk factors and downstream clinical outcomes and explains why interventions aimed at either of these components have limited success. Potential therapeutic approaches are considered based on this model. Because telomerase activity can prevent and reverse cell senescence, telomerase gene therapy is discussed as a promising intervention. Telomerase gene therapy and similar systems interventions based on the unified model are expected to be transformational in cardiovascular medicine.

Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank.

Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer's disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer's Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer's therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic.

Cell senescence in human aging and disease.

The most common causes of death and suffering, even in most underdeveloped nations, are age-related diseases. These diseases share fundamental and often unappreciated pathology at the cellular and genetic levels, through cell senescence. In cancer, enforcing cell senescence permits us to kill cancer cells without significantly harming normal cells. In other age-related diseases, cell senescence plays a direct role, and we may be able to prevent and reverse much of the pathology. While aging is attributed to "wear and tear," genetic studies show that these effects are avoidable (as is the case in germ cell lines) and occur only when cells down-regulate active (and sufficient) repair mechanisms, permitting degradation to occur. Aging occurs when cells permit accumulative damage by wear and tear, by altering their gene expression rather than vice versa. Using telomerase in laboratory settings, we can currently reset this pattern and its consequences both within cells and between cells. Doing so resets not only cell behavior but the pathological consequences within tissues comprising such cells. We can currently grow histologically young, reconstituted human skin using old human skin cells (keratinocytes and fibroblasts). Technically we could now test this approach in joints, vessels, the immune system, and other tissues. This model is consistent with all available laboratory data and known aging pathology. Within the next decade, we will be able to treat age-related diseases more effectively than ever before.

Is there an antiaging medicine?

In spite of considerable hype to the contrary, there is no convincing evidence that currently existing so-called "antiaging" remedies promoted by a variety of companies and other organizations can slow aging or increase longevity in humans. Nevertheless, a variety of experiments with laboratory animals indicate that aging rates and life expectancy can be altered. Research going back to the 1930s has shown that caloric restriction (also called dietary restriction) extends life expectancy by 30-40% in experimental animals, presumably at least partially by delaying the occurrence of age-dependent diseases. Mutations that decrease production of insulin growth factor I in laboratory mammals, and those that decrease insulin-like signaling in nematodes and fruit flies, have increased life expectancy as well. Other general strategies that appear promising include interventions that reduce oxidative stress and/or increase resistance to stress; hormone and cell replacement therapies may also have value in dealing with specific age-related pathologies. This article reports the findings of a consensus workshop that discussed what is known about existing and future interventions to slow, stop, or reverse aging in animals, and how these might be applied to humans through future research.

Anti-aging teleconference: what is anti-aging medicine?

The concepts of "anti-aging" and "anti-aging medicine" in particular are hotly debated now, both in the mass media and among some researchers. This paper represents an open discussion of anti-aging terms and related ideas by nine leading experts in the field of aging studies, and it describes in detail the arguments presented by both supporters and opponents of these concepts. Candid exchange of opinions makes it clear that more efforts are required before a consensus on these issues can be reached. The paper also presents evidence that the term "anti-aging" is routinely used now in scientific literature as a legitimate scientific term, including even the titles of publications in reputable scientific journals, written by established researchers.