Energy metabolism, altered proteins, sirtuins and ageing: converging mechanisms?

The predominant molecular symptom of ageing is the accumulation of altered gene products. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin activity. Physiological and other approaches indicate that mitochondria may also regulate ageing. A mechanism is proposed which links diet, exercise and mitochondria-dependent changes in NAD/NADH ratio to intracellular generation of altered proteins. It is suggested that ad libitum feeding conditions decrease NAD availability which also decreases metabolism of the triose phosphate glycolytic intermediates, glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate, which can spontaneously decompose into methylglyoxal (MG). MG is a highly toxic glycating agent and a major source of protein advanced-glycosylation end-products (AGEs). MG and AGEs can induce mitochondrial dysfunction and formation of reactive oxygen species (ROS), as well as affect gene expression and intracellular signalling. In dietary restriction–induced fasting, NADH would be oxidised and NAD regenerated via mitochondrial action. This would not only activate sirtuins and extend lifespan but also suppress MG formation. This proposal can also explain the apparent paradox whereby increased aerobic activity suppresses formation of glycoxidized proteins and extends lifespan. Variation in mitochondrial DNA composition and consequent mutation rate, arising from dietary-controlled differences in DNA precursor ratios, could also contribute to tissue differences in age-related mitochondrial dysfunction.     

Mitochondrial dysfunction and cell senescence: cause or consequence?

The mitochondrial theory of aging remains to date one of the most popular theories of aging. One major model of aging is replicative senescence, where the irreversible loss of division potential of somatic cells occurs after a more or less constant number of cell divisions. Few data are available concerning the role of mitochondria in this model. Here, we review evidence supporting the involvement of mitochondria in replicative senescence and a possible link to telomere biology. Moreover, we suggest that this process might be more complex than originally formulated, because variations in nuclear gene expression involved in mitochondrion nucleus cross-talk are observed in both senescence and immortalization.     

What mechanisms underlie diastolic dysfunction in heart failure?

Abnormalities of diastolic function are common to virtually all forms of cardiac failure. However, their underlying mechanisms, precise role in the generation and phenotypic expression of heart failure, and value as specific therapeutic targets remain poorly understood. A growing proportion of heart failure patients, particularly among the elderly, have apparently preserved systolic function, and this is fueling interest for better understanding and treating diastolic abnormalities. Much of the attention in clinical and experimental studies has focused on relaxation and filling abnormalities of the heart, whereas chamber stiffness has been less well studied, particularly in humans. Nonetheless, new insights from basic and clinical research are helping define the regulators of diastolic dysfunction and illuminate novel targets for treatment. This review puts these developments into perspective with the major aim of highlighting current knowledge gaps and controversies.     

AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?

In Alzheimer's disease, age-related cellular changes such ascompromised energy production and increased radical formation areworsened by the presence of AGEs as additional, AD specificstress factors. Intracellular AGEs (most likely derived frommethylglyoxal) crosslink cytoskeletal proteins and render theminsoluble. These aggregates inhibit cellular functions includingtransport processes and contribute to neuronal dysfunction anddeath. Extracellular AGEs, which accumulate in ageing tissue (butmost prominently on long-lived protein deposits like the senileplaques) exert chronic oxidative stress on neurons. In addition,they activate glial cells to produce free radicals (superoxideand NO) and neurotoxic cytokines such as TNF-. Drugs, whichinhibit the formation of AGEs by specific chemical mechanisms(AGE-inhibitors), including aminoguanidine, carnosine,tenilsetam, OPB-9195 and pyridoxamine, attenuate the developmentof (AGE-mediated) diabetic complications. Assuming that `carbonylstress' contributes significantly to the progression ofAlzheimer's disease, AGE-inhibitors might also becomeinteresting novel therapeutic drugs for treatment of AD.     

Health and ageing in Australia: Is there culture after sixty?

This paper examines health and ageing in Australia using the concept of culture as a constitutive human process through which people create specific and different ways of life. Beliefs about and attitudes towards frailty and ill health among the old, and their associated practices, form the unifying theme. The ways in which such beliefs and practices are necessarily connected with material social structures and processes (especially class and gender relations) are emphasised.     

β-Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes

Diabetes mellitus is etiologically classified into type 1, type 2 and other types of diabetes. Despite distinct etiologies and pathogenesis of these subtypes, many studies have suggested the presence of shared susceptibilities and underlying mechanisms in β-cell failure among different types of diabetes. Understanding these susceptibilities and mechanisms can help in the development of therapeutic strategies regardless of the diabetes subtype. In this review, we discuss recent evidence indicating the shared genetic susceptibilities and common molecular mechanisms between type 1, type 2 and other types of diabetes, and highlight the future prospects as well.     

Does acute organ dysfunction predict patient-centered outcomes?

BACKGROUND: Long-term patient-centered outcomes after acute illness may be associated with baseline health status, the development of acute organ dysfunction (AOD), or both. STUDY OBJECTIVE: To determine whether AOD (occurring in the first 30 days) was independently associated with 90-day survival, functional status, and health-related quality of life (HRQL) after controlling for baseline health status in patients who were hospitalized with community-acquired pneumonia (CAP) and survived to day 30. DESIGN: Prospective observational study. SETTING: Four hospitals in Pennsylvania, Massachusetts, and Nova Scotia, Canada, between October 1991 and March 1994. PATIENTS: One thousand three hundred thirty-nine patients who were hospitalized with CAP. INTERVENTIONS: Baseline and 90-day quality-of-life and functional status questionnaires. MEASUREMENTS AND RESULTS: We determined the 90-day survival rate in all patients (n = 1,339) and the functional status and HRQL in subsets of 261 and 219 patients, respectively. AOD occurred in one or more organ system in 639 patients (47.7%) and in two or more organ systems in 255 patients (19.1%). In univariate analyses, greater AOD was associated with a higher mortality rate (p < 0.0001), a lower HRQL (p = 0.006), and lower functional status (p = 0.009) at 90 days. However, after adjusting for baseline HRQL, AOD was not associated with mortality (p = 0.47) or HRQL (p = 0.14) at 90 days and was only weakly associated with 90-day functional status (p = 0.02). CONCLUSIONS: Although patients who develop AOD are at risk for late adverse outcomes, their risk is due predominantly to poor baseline status prior to illness and not to the organ dysfunction per se. Therefore, AOD does not appear to have significant long-term ramifications for patient-centered outcomes.