Impaired adaptive receptor regulation: an index of aging?

Many neuroendocrine functions are altered in old animals and their study may represent important steps in the understanding of the mechanisms of aging. A deeper insight, however, can be achieved by investigating the responsiveness to stimuli, which may reveal alterations not evident in the unstimulated conditions. At this level of study, many of such impairments have been found to be caused by receptor changes. In the present paper a third level of study is suggested in order to gain evidence of some remote failure of adaptive processes strictly linked to intimate mechanisms of aging. As at the second level of study different receptor characteristics can frequently be found at the basis of age-related alterations of biological responsiveness, at the proposed third level altered capacity of receptor regulation may be hypothesized as responsible for altered cell adaptation following hormone and drug stimuli. Experimental data are given which support this view. The possibility that receptor regulation may be used as an index of aging is suggested. This hypothesis leads to the problem of judging the validity of biological parameters deputed to represent good indices of aging. In order to solve this problem, the potential use of a mathematical model of mortality kinetics is discussed.     

Mitochondrial mutations in mammalian aging: an over-hasty about-turn?

The very low abundance of mitochondrial DNA (mtDNA) mutations in nearly all mammalian tissues even in old age has led most mitochondriologists to reject the idea that such mutations might have a causal role in aging, despite (1) the strong circumstantial (e. g., interspecies) evidence that they do have such a role, (2) the promulgation since 1998 of two detailed mechanisms whereby low levels of mtDNA mutations could be harmful, and (3) the report of a transgenic mouse with cardiomyopathy apparently caused by artificially high levels of mtDNA mutations in the heart. A recent report of a mouse with ubiquitously accelerated accumulation of mtDNA mutations and an array of phenotypes reminiscent of aging has abruptly overturned this consensus, with not only the authors but also many other expert commentators suggesting that the mtDNA mutation theory of aging has risen from the ashes. However, there are compelling reasons to doubt the relevance of this mouse to normal mammalian aging, and thus to seek further testing of specific mechanistic hypotheses for how mtDNA mutations could cause age-related dysfunction.     

Arterial aging: is it an immutable cardiovascular risk factor?

Age is the dominant risk factor for cardiovascular diseases. However, until recently, convincing mechanistic or molecular explanations for the increased cardiovascular risks conferred by aging have been elusive. Aging is associated with alterations in a number of structural and functional properties of large arteries, including diameter, wall thickness, wall stiffness, and endothelial function. Emerging evidence indicates that these age-associated changes are also accelerated in the presence of cardiovascular diseases, and that these changes are themselves risk factors for the appearance or progression of these diseases. In this review, the evidence demonstrating that arterial aging is accelerated in cardiovascular diseases and that accelerated arterial aging is a risk factor for adverse cardiovascular outcomes is briefly reviewed, and selected advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging are summarized. Remarkably, a host of biochemical, enzymatic, and cellular alterations that are operative in accelerated arterial aging have also been implicated in the pathogenesis and progression of arterial diseases. These vascular alterations are thus putative candidates that could be targeted by interventions aimed at attenuating arterial aging, similar to the lifestyle and pharmacological interventions that have already been proven effective. Therefore, the notion that aging is a chronological process and that its risky components cannot be modulated is no longer tenable. It is our hope that a greater appreciation of the links between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging.     

Changes of cortico-muscular coherence: an early marker of healthy aging?

Cortico-muscular coherence (CMC) at beta frequency (13–30 Hz) occurs particularly during weak to moderate isometric contraction. It is a well-established measure of communication between the primary motor cortex (M1) and corresponding muscles revealing information about the integrity of the pyramidal system. Although the slowing of brain and muscle dynamics during healthy aging has been evidenced, functional communication as determined by CMC has not been investigated so far. Since decline of motor functions at higher age is likely to be associated with CMC changes, the present study aims at shedding light on the functionality of the motor system from a functional interaction perspective. To this end, CMC was investigated in 27 healthy subjects aging between 22 and 77 years during isometric contraction of their right forearm. Neuromagnetic activity was measured using whole-head magnetoencephalography (MEG). Muscle activity was measured by means of surface electromyography (EMG) of the right extensor digitorum communis (EDC) muscle. Additionally, MEG-EMG phase lags were calculated in order to estimate conducting time. The analysis revealed CMC and M1 power amplitudes to be increased with age accompanied by slowing of M1, EMG, and CMC. Frequency changes were particularly found in subjects aged above 40 years suggesting that at this middle age, neurophysiological changes occur, possibly reflecting an early neurophysiological marker of seniority. Since MEG–EMG phase lags did not vary with age, changes cannot be explained by alterations of nerve conduction. We argue that the M1 power amplitude increase and the shift towards lower frequencies might represent a neurophysiological marker of healthy aging which is possibly compensated by increased CMC amplitude.     

The biological aging is our inescapable fate – but can we modify it?

The quest for postponing ageing has been in the mind of man since the earliest civilisations and the ancient symbols (healing water, herbs, sleep and the snake) are also found in the attempts undertaken today. Maximum life span, however, has not changed much due to these efforts. The rate of increase has been estimated to be about 10 year per million years. Mean life span has, on the other hand, increased dramatically, due to major environmental improvements, from about 30 to 80 years. Much of this increase is due to decrease in childhood and early adulthood mortality and has occurred during the last 130 years. Whether and to what extent this increase will continue is not clear. The complexity of the human genome is discussed together with current knowledge of gene technology and ethical problems in this context. Life extension in primitive animals with much simpler genomes, and inheritable diseases with premature ageing in man are used as examples for how new knowledge can be gained in this field. Transgenic animals and knockout mice are used as examples for progress in gene technology. It is emphasised that at present the best possibilities to ameliorate the effects of the ageing processes are having a healthy lifestyle, which includes a balanced diet, avoiding being overweight, drinking some red wine and doing a moderate amount of physical exercise.     

Is there an advanced aging effect on the ability to mentally represent action?

Motor programming theory suggests that an integral component in an effective outcome is an adequate action (mental) representation of the movements; a representation reflected in the ability to use motor imagery. Recent reports show a decline with advanced age (>64 years) using a variety of motor simulation tasks. Here, we examined the possible effects of advanced age on motor imagery ability in the context of estimation of reachability - that is, estimating whether an object is within reach or out of grasp. Thirty young adults (mean age: 20) and 23 older adults (mean age: 77) were instructed to estimate, using motor imagery, whether randomly presented targets in peripersonal (within actual reach) and extrapersonal (beyond reach) space were within or out of reach of their dominant limb while seated. Results indicated that the younger group was significantly more accurate than the older adults, p < 0.001. Whereas both groups made more errors in extrapersonal space, the values were significantly higher for the older group; that is, they overestimated to a greater extent. In summary, these findings add to the general notion that there is a decline in the ability to mentally represent action with advanced age.     

Is mammalian aging genetically controlled?

The rate of aging is species-specific, indicating that aging has a strong genetic component. Amongst mammals, the synchronization of the aging process suggests the presence of genetic determinants. In addition, single gene manipulations can change the rate of aging and demonstrate how a few genetic factors can regulate aging. Therefore, I propose that aging is regulated by a small set of genetic mechanisms, a single clock. If we can find what these regulatory mechanisms are, then instead of trying to delay age-related pathologies one by one we may be able to discover how to delay the entire aging process and most, if not all, of its pathologies. This revised version was published online in July 2006 with corrections to the Cover Date.