The spindle checkpoint monitors the interaction between spindle microtubules and kinetochores to prevent precocious entry into anaphase, delaying this stage of mitosis until all condensed chromosomes have been attached to the mitotic spindle in a bi-oriented manner (so that the two kinetochores associated with a pair of sister chromatids are oriented toward opposite poles of the spindle). In addition to conserved Bub and Mad family members, which are known to function in the spindle checkpoint pathway in organisms ranging from yeast to mammals, two mRNA transport genes, Rae1 and Nup9 , are also involved in the spindle checkpoint function in mammals. Biochemically, activated spindle checkpoint components have been shown to suppress the activity of the anaphase promoting complex/cyclosome. It is generally thought that decreased activity of the checkpoint components predisposes cells to chromosomal instability, aneuploidy, and malignant transformation. Interestingly, a recent study has shed light on a new function of the spindle checkpoint components Bub3 and Rae1 in the regulation of aging. Mice with haploinsufficiency of Bub3 and Rae1 have a short life span that is associated with the early onset of aging-related features. The progeroid phenotypes caused by deficiency of Bub3 and Rae1 are tightly linked to precocious activation of cellular senescence, but not apoptotic, programs. Therefore, premature aging, rather than neoplastic transformation, may be the major manifestation of a compromised spindle checkpoint in vivo.
A wide range of animal and human studies provide evidence for the potential of physical and cognitive exercise in promoting cognitive health later in life. The effects of such activities on intermediate outcomes, such as cognitive performance, are becoming clearer, as are the molecular mechanisms involved. Physical and cognitive exercise might increase "cognitive reserve" and increase the overall health of the brain, thereby reducing or delaying cognitive impairment and dementia. However, conclusive evidence for such benefits is not yet established. The third annual Bedside to Bench conference, cosponsored by The American Geriatrics Society and the National Institutes of Health's National Institute on Aging, reviewed current knowledge regarding the role of physical and cognitive exercise in promoting cognitive vitality. Conference attendees identified gaps in our current understanding of these processes and recommended next steps for research. In particular, researchers will need to explore clinical issues related to the timing, intensity, and duration of various types and combinations of physical and cognitive activities in animal models to elucidate the mechanisms involved and inform the design of future human studies. The concept of the enriched environment currently employed in animal studies to promote physical activity, socialization, and problem solving should be explored in human studies.
klotho mutant mice were originally described as a short-lived mouse model with premature aging-like disorders. The klotho gene responsible for these phenotypes encodes a type I membrane protein with a considerable similarity to beta-glycosidase. klotho is predominantly expressed in tissues functioning in the regulation of calcium homeostasis. Suggested functions of Klotho are (i) a fundamental regulator of calcium homeostasis, namely, a cofactor for the fibroblast growth factor (FGF) receptor 1c in FGF23 signaling and a regulator of parathyroid hormone secretion; (ii) a hormone that interferes with the intracellular signaling of insulin and insulin-like growth factor-1; and (iii) a beta-glucuronidase that activates the transient receptor potential ion channel TRPV5 by trimming its sugar moiety. How can we reconcile these pleiotropic functions of Klotho? Is there any common mechanism? Further in vivo studies, and biochemical as well as physiological analyses, are required for a better understanding of the molecular aspects of Klotho.
Sugars tantalize our taste buds and fuel our cells, but we pay a price for relying on the sweet, energy-rich molecules. Glucose and its breakdown products--especially one called methylglyoxal--can gum up vital cellular components. In the last 10 to 15 years, methylglyoxal and its chemical cousins have grabbed the attention of experts studying diabetes, cancer, and other diseases. One new paper suggests that methylglyoxal undermines health in an unexpected way: by altering the activity of a gene that controls blood vessel growth, possibly triggering one complication of diabetes. Scientists suspect that methylglyoxal disrupts the activity of other genes as well.
Like shipwrecked sailors, famished cells sometimes turn to cannibalism. Rather than eating their mateys, though, they devour their own contents. A previously overlooked protein boosts cancer cells' appetite, triggering them to commit suicide, according to a new study. The research solidifies the controversial connection between self-consumption and cancer.
Slicing messenger RNA molecules in the wrong position cuts short the lives of children with a disease that resembles speedy aging, and new research suggests that cells from old people make the same mistake. The finding implies that normal aging shares a mechanism with the rare genetic ailment.
Coaches can hurt their athletes by working them out too long or too hard. Similarly, a protein that keeps testicles making sperm wears down the organ, new research shows. The results suggest a new tactic to prevent testicle damage.
Defying evolutionary orthodoxy that aging is a disorderly collapse, some researchers argue that the process is an adaptation. Many of these scientists posit that group selection, a controversial form of natural selection in which the group's interests take precedence over those of the individual, drives the evolution of aging. To support their contention that senescence is genetically programmed, the researchers list evidence such as the existence of mutant organisms that live longer than normal, which suggests that unaltered creatures are "voluntarily" dying. Most evolutionists scoff at programmed aging and group selection, which conflict with the prevailing view that natural selection favors traits that benefit individuals over groups. Other scientists are probing whether aging helps reduce competition between relatives, a less controversial alternative to group selection.
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.
For one hundred years after Alois Alzheimer's first report of Alzheimer's disease (AD) in 1906, the pathological hallmarks of the disease, senile plaques and neurofibrillary tangles (NFTs), have been attractive targets for researchers. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the cell biology of amyloid-beta (Abeta) deposition as senile plaques or on the phosphorylation and aggregation of tau as NFTs. However, it now appears that this focus on pathology as a central contributor to disease may be misguided. Indeed, neurons associated with Abeta and NFTs in AD brain show a decrease in oxidative damage relative to those in vulnerable but morphologically intact areas of the brain, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. That Abeta and tau accumulations indicate an age-related physiological reaction to chronic stress calls into question the rationale of current therapeutic efforts targeted toward lesion removal. Moreover, if this concept holds true for pathology in other neurodegenerative diseases, we may need to restructure our thinking and undergo a paradigm shift before substantial progress can be made in therapeutic intervention.
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.
The cyclin-dependent kinase-5 (Cdk5) is critical to normal mammalian development and has been implicated in synaptic plasticity, learning, and memory in the adult brain. But Cdk-5 activity has also been linked to neurodegenerative diseases. Could a single protein have opposing effects? A new study shows that production of a neuronal protein capable of regulating Cdk-5 activity can turn Cdk-5 from "good" to "bad." The findings may have implications for the development and treatment of conditions like Alzheimer's disease.
Insulin resistance, a condition in which body cells quit heeding the hormone, is a stop on the road to type 2 diabetes and a possible heart attack. But a new study of mice indicates that if particular immune cells become unresponsive to insulin, they help fend off one lethal complication of diabetes: atherosclerosis. The work suggests that insulin resistance in these cells curtails inflammation that promotes arterial obstructions.
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.
The aging-related research field has focused on the detection of genetic factors that affect the aging process, but more recently scientists have started to shift their attention to novel and more integrative ways of studying cellular and organismal function. Such approaches allow them to uncover and explore unexpected patterns and themes, resulting in a more comprehensive knowledge of the complex regulatory pathways and networks involved in aging and age-related diseases. Eventually, this knowledge will lead to a systems-level understanding of aging. The third "Functional Genomics of Aging" conference held in Palermo, Italy, in March/April 2006 highlighted some of the more exciting work in this area.
In some family businesses, one heir will strike out in a new direction, rejecting his or her expected fate. Similarly, a protein whose kin protect animals from cancer instead seems to guard mice against a metabolic disruption. The results show that flawed DNA repair could contribute to a condition called metabolic syndrome, and they support a link between the condition and mitochondria.
Small-fiber neuropathy is a peripheral nerve disease that most commonly presents in middle-aged and older people, who develop burning pain in their feet. Although it can be caused by disorders of metabolism such as diabetes, chronic infections (such as with human immunodeficiency virus), genetic abnormalities, toxicity from various drugs, and autoimmune diseases, the cause often remains a mystery because standard electrophysiologic tests for nerve injury do not detect small-fiber function. Inadequate ability to test for and diagnose small-fiber neuropathies has impeded patient care and research, but new tools offer promise. Infrequently, the underlying cause of small-fiber dysfunction is identified and disease-modifying therapy can be instituted. More commonly, the treatments for small-fiber neuropathy involve symptomatic treatment of neuropathic pain.
Calorie restriction (CR) tunes up metabolism and makes animals more active. However, the regimen has drawbacks, such as sensitivity to cold and loss of reproduction. Some animals don't gain time, and CR might not work for old individuals. Researchers don't have a full-fledged theory for how CR works, but some scientists postulate that the diet extends life by activating a stress-fighting response. Some researchers argue that we are close to understanding one molecular mechanism behind that effect that involves the enzyme Sir2p. Recent work questions the Sir2p connection and supports an alternative, the TOR pathway. Fat and leaky mitochondria might also play a role in CR. An upcoming study might clarify the diet's benefits for humans.
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.
Cancer affects two major cell types in the human skin: epithelial cells and melanocytes. Aging and a previous history of ultraviolet light exposure are major risk factors for skin cancers, including basal and squamous cell carcinomas and melanomas. However, melanomas, which are the most deadly of the skin tumors, display two intriguing characteristics: The incidence is increased and the prognosis is worse in males over 60 years as compared with females of the same age. This Perspective discusses possible reasons for age and gender as melanoma risk factors, as well as the need for studies aimed at unraveling the molecular mechanism of such puzzling events.
