Elsevier

Cell Calcium

Volume 34, Issues 4–5, October–November 2003, Pages 311-323
Cell Calcium

Neuronal ageing from an intraneuronal perspective: roles of endoplasmic reticulum and mitochondria

https://doi.org/10.1016/S0143-4160(03)00142-8Get rights and content

Abstract

The nature of brain ageing and the age-dependent decline in cognitive functions remains poorly understood. Physiological brain ageing is characterised by mild mental dysfunctions, whereas age-dependent neurodegeneration, as illustrated by Alzheimer disease (AD), results rapidly in severe dementia. These two states of the aged brain, the physiological and the pathological, are fundamentally different as the latter stems from significant neuronal loss, whereas the former develops without significant neuronal demise. In this paper, we review the changes in neuronal Ca2+ homeostasis that occur during brain ageing, and conclude that normal, physiological ageing is characterised mainly by a decrease of neuronal homeostatic reserve, defined as the capacity to respond effectively to functional and metabolic stressors, but does not reach the trigger required to induce neuronal death. In contrast, during neurodegenerative states, Ca2+ homeostasis is affected early during the pathological process and result in significant neuronal demise. We also review recent evidence suggesting that the endoplasmic reticulum (ER) might play an important role in controlling the balance between healthy and pathological neuronal ageing.

Introduction

The gift of life comes at some expense and the price of living is the imminence of the end. For most, the other price of living is the inexorable ageing, that affects body and mind. Yet, the progressive mental decline of ageing is by no means universal, and mankind experience shows that the effects of age on cognitive functions can be counteracted by continuous mental exercise. Alas, this recipe does not always work and, as the biographies of prominent English writers Cecilia Wedgwood and Iris Murdoch show, neurodegenerative disorders, most frequently manifested in the form of Alzheimer disease (AD), affect a considerable proportion of the population.

Various factors determined in brain ageing will assume a physiological (normal) or pathological route and understanding the cellular and molecular processes responsible for these two forms of brain ageing is of ultimate importance, as it lays the background for therapeutic strategies against the pathological route and for enhancing our chances to impede the cognitive decline of physiological brain ageing.

There are many hypotheses regarding the nature and the mechanisms of normal ageing. The causes that have been proposed to explain the natural process of ageing range enormously, from the basic molecular levels (e.g. DNA mutations) to cellular levels (e.g. metabolic dysfunctions and accumulation of toxic products) and further, to system levels (e.g. alterations in the immune response). An even wider biological perspective is provided by the hypotheses of ageing based on evolutionary theory (e.g. “disposable soma” theory). This multiplicity of explanations reflects the multi-factorial nature of this complex process.

In this review, we will take a cellular physiology perspective on neuronal ageing. If we define the capacity of the neurones to respond to functional and metabolic stressors as their “homeostatic reserve”, in our model, normal ageing is seen as a functional physiological state characterised by a decrease in their homeostatic reserve. An important issue of our working hypothesis is that the decrease in homeostatic reserve with age does not affect the functional resting state of the neurones or the base-line level of neuronal activity, and it becomes relevant and a limiting factor only in conditions of excessive activity or when other ethio-pathogenic factors become superimposed, as is the case with the neurodegenerative disease. This perspective on ageing as a state of decreased homeostatic reserve is in line with the current view that normal brain ageing is not associated with significant neuronal losses, which is characteristic for the later stages of neurodegenerative diseases [1]. In fact, the relationship between cellular changes in normal ageing and the neurodegenerative diseases pathology is much less investigated currently than the actual pathology itself. In many of the neurodegenerative diseases there is a strong genetic background, but the accumulation of pathological features appears only from middle age onwards. One explanation would be that the modified proteins characteristic for these neurodegenerative disorders require time to accumulate in strategic regions before triggering the clinical signs. Another possibility is that the expression of these ethio-pathogenic mechanisms of neurodegeneration could be fully expressed only in neurones affected by the ageing process, that is, in neurones with a decreased homeostatic reserve. Thus, in the relationship between ageing and neurodegenerative diseases, ageing should be seen as the functional background against which the factors specific for ND diseases act, resulting in the specific pathology. Another facet of the decreased homeostatic reserve of aged neurones is illustrated by the increased vulnerability of older neurones (e.g. [2]).

Section snippets

Ca2+ homeostasis in ageing

It is an established paradigm of current cellular physiology that changes in the free Ca2+ concentration ([Ca2+]i) in various cellular subcompartments act as a universal signalling system, connected to most cellular functions [3], [4], [5], [6], [7]. It is no surprise then that one area of neuronal physiology of ageing that received significant attention in the last 10–15 years was that of Ca2+ homeostasis. One contributing factor was the persuasive “Ca2+ hypothesis of ageing” proposed by

Endoplasmic reticulum as a universal signalling organelle

The endoplasmic reticulum is the largest intracellular organelle, formed by a complex system of endomembranes. The ER is present in all neurones, where it forms a continuous network occupying the cell somata, and extending towards the axons, dendrites and dendritic spines [66], [67]. The ER serves not only as an indispensable dynamic Ca2+ store, but it also regulates post-translational protein processing occurring in the ER lumen and generates various signalling events controlling long-lasting

Changes in mitochondrial status associated with ageing

The data presented up to here, showing the delayed recovery of resting [Ca2+]i following stimulation and the reduction in the ER Ca2+ content that appear to characterise normal neuronal ageing, might all be accounted for by a relative decrease in the energetic reserve of the aged neurones, since all the processes that participate in the removal of Ca2+ from cytosol or its uptake into the ER are, ultimately, dependent on ATP, either directly, as the PMCA or the SERCA, or indirectly, as is the

Factors affecting mitochondrial status

Although mtDNA mutations have been detected in a wide range of human and animal tissues, it is still relatively poorly understood how they occur, and to date the best candidate is the oxidative stress, i.e. the mutagen effect of the reactive oxygen species (ROS, or free radicals). In fact the relationship between mitochondrial function, that includes their capacity to generate free radicals, and ROS is central to a number of cellular theories of ageing, including the The Free Radicals Theory

Conclusions

Ageing is a multi-factorial process to which a variety of genetic, biological and environmental factors contribute. A general overview of the data available concerning the cellular physiology of neuronal ageing indicate that, overall, the major functional characteristic of the aged neurones is a decrease in their capacity to respond to functional and metabolic stressors, a capacity that we call the ‘homeostatic reserve’. As a result of this decrease in their homeostatic reserve, the aged

Acknowledgements

Our ageing research was supported by BBSRC.

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