The aging feline kidney: a model mortality antagonist?

Traditional thinking views apparently non-programmed disruptions of aging, which medical science calls geriatric diseases, as separate from 'less harmful' morphological and physiological aging phenotypes that are more universally expected with passage of time (loss of skin elasticity, graying of hair coat, weight gain, increased sleep time, behavioral changes, etc). Late-life disease phenotypes, especially those involving chronic processes, frequently are complex and very energy-expensive. A non-programmed process of homeostatic disruption leading into a death trajectory seems inconsistent with energy intensive processes. That is, evolutionary mechanisms do not favor complex and prolonged energy investment in death. Taking a different view, the naturally occurring feline (Felis silvestris catus) renal model suggests that at least some diseases of late life represent only the point of failure in essentially survival-driven adaptive processes. In the feline renal model, individuals that succumbed to failure most frequently displayed progressive tubular deletion and peritubular interstitial fibrosis, but had longer mean life span than cats that died from other causes. Additionally, among cats that died from non-renal causes, those that had degrees of renal tubular deletion and peritubular interstitial fibrosis also had longer mean life span than those cats with no changes, even though causes of death differed minimally between these latter two groups. The data indicate that selective tubular deletion very frequently begins early in adult life, without a clear initiating phase or event. The observations support a hypothesis that this prolonged process may be intrinsic and protective prior to an ultimate point of failure. Moreover, given the genetic complexity and the interplay with associated risk factors, existing data also do not support the ideas that these changes are simple compensatory responses and that breed- or strain-based 'default' diseases are inevitable results of increasing individual longevity. Emerging molecular technology offers the future potential to further evaluate and refine these observations. At present, the existence of plastic and adaptive aging programming is suggested by these findings.

Aging is a deprivation syndrome driven by a germ-soma conflict.

Evolution through natural selection can be described as driven by a perpetual conflict of individuals competing for limited resources. Recently, I postulated that the shortage of resources godfathered the evolutionary achievements of the differentiation-apoptosis programming [Rev. Neurosci. 12 (2001) 217]. Unicellular deprivation-induced differentiation into germ cell-like spores can be regarded as the archaic reproduction events which were fueled by the remains of the fratricided cells of the apoptotic fruiting body. Evidence has been accumulated suggesting that conserved through the ages as the evolutionary legacy of the germ-soma conflict, the somatic loss of immortality during the ontogenetic segregation of primordial germ cells recapitulates the archaic fate of the fruiting body. In this heritage, somatic death is a germ cell-triggered event and has been established as evolutionary-fixed default state following asymmetric reproduction in a world of finite resources. Aging, on the other hand, is the stress resistance-dependent phenotype of the somatic resilience that counteracts the germ cell-inflicted death pathway. Thus, aging is a survival response and, in contrast to current beliefs, is antagonistically linked to death that is not imposed by group selection but enforced upon the soma by the selfish genes of the "enemy within". Environmental conditions shape the trade-off solutions as compromise between the conflicting germ-soma interests. Mechanistically, the neuroendocrine system, particularly those components that control energy balance, reproduction and stress responses, orchestrate these events. The reproductive phase is a self-limited process that moulds onset and progress of senescence with germ cell-dependent factors, e.g. gonadal hormones. These degenerate the regulatory pacemakers of the pineal-hypothalamic-pituitary network and its peripheral, e.g. thymic, gonadal and adrenal targets thereby eroding the trophic milieu. The ensuing cellular metabolic stress engenders adaptive adjustments of the glucose-fatty acid cycle, responses that are adequate and thus fitness-boosting under fuel shortage (e.g. during caloric restriction) but become detrimental under fuel abundance. In a Janus-faced capacity, the cellular stress response apparatus expresses both tolerogenic and mutagenic features of the social and asocial deprivation responses [Rev. Neurosci. 12 (2001) 217]. Mediated by the derangement of the energy-Ca(2+)-redox homeostatic triangle, a mosaic of dedifferentiation/apoptosis and mutagenic responses actuates the gradual exhaustion of functional reserves and eventually results in a multitude of aging-related diseases. This scenario reconciles programmed and stochastic features of aging and resolves the major inconsistencies of current theories by linking ultimate and proximate causes of aging. Reproduction, differentiation, apoptosis, stress response and metabolism are merged into a coherent regulatory network that stages aging as a naturally selected, germ cell-triggered and reproductive phase-modulated deprivation response.

A unifying hypothesis of Alzheimer's disease. III. Risk factors.

Normal ageing and Alzheimer's disease (AD) have many features in common and, in many respects, both conditions only differ by quantitative criteria. A variety of genetic, medical and environmental factors modulate the ageing-related processes leading the brain into the devastation of AD. In accordance with the concept that AD is a metabolic disease, these risk factors deteriorate the homeostasis of the Ca(2+)-energy-redox triangle and disrupt the cerebral reserve capacity under metabolic stress. The major genetic risk factors (APP and presenilin mutations, Down's syndrome, apolipoprotein E4) are associated with a compromise of the homeostatic triangle. The pathophysiological processes leading to this vulnerability remain elusive at present, while mitochondrial mutations can be plausibly integrated into the metabolic scenario. The metabolic leitmotif is particularly evident with medical risk factors which are associated with an impaired cerebral perfusion, such as cerebrovascular diseases including stroke, cardiovascular diseases, hypo- and hypertension. Traumatic brain injury represents another example due to the persistent metabolic stress following the acute event. Thyroid diseases have detrimental sequela for cerebral metabolism as well. Furthermore, major depression and presumably chronic stress endanger susceptible brain areas mediated by a host of hormonal imbalances, particularly the HPA-axis dysregulation. Sociocultural and lifestyle factors like education, physical activity, diet and smoking may also modulate the individual risk affecting both reserve capacity and vulnerability. The pathophysiological relevance of trace metals, including aluminum and iron, is highly controversial; at any rate, they may adversely affect cellular defences, antioxidant competence in particular. The relative contribution of these factors, however, is as individual as the pattern of the factors. In familial AD, the genetic factors clearly drive the sequence of events. A strong interaction of fat metabolism and apoE polymorphism is suggested by intercultural epidemiological findings. In cultures, less plagued by the 'blessings' of the 'cafeteria diet-sedentary' Western lifestyle, apoE4 appears to be not a risk factor for AD. This intriguing evidence suggests that, analogous to cardiovascular diseases, apoE4 requires a hyperlipidaemic lifestyle to manifest as AD risk factor. Overall, the etiology of AD is a key paradigm for a gene-environment interaction. Copyright 2000 John Wiley & Sons, Ltd.

Chronic tension-type headache: amitriptyline reduces clinical headache-duration and experimental pain sensitivity but does not alter pericranial muscle activity readings.

In a double-blind, placebo-controlled trial, the effect of 75 mg of a slow-release formulation of amitriptyline on the clinical severity of chronic tension-type headache and on headache-associated neurophysiological parameters (EMG activity, exteroceptive suppression of temporal muscle activity, contingent negative variation (CNV) and experimental pain sensitivity) was investigated. All of the patients treated had a history of headaches of many years' standing and many of them had failed attempts at treatment. In the amitriptyline group, a significant reduction in daily headache duration was already found in the 3rd week of treatment, while in the placebo group no significant changes in headache duration were to be seen. In week 6 the amitriptyline group had a significantly shorter daily duration of headache than did the placebo group. Treatment did not result in any significant effects on EMG recordings of pericranial muscle activity either during relaxation or contraction, on exteroceptive suppression of the temporal muscle and on CNV. The sensitivity to suprathreshold experimental pain, however, was significantly reduced. The data show a statistically relevant reduction of daily headache duration. However, they also show that amitriptyline can only partly alleviate chronic headaches but cannot cure them.