Life After 60 - A Guide - Part II

By Rakesh Mittal

Senior Citizens enter an unchartered territory at eligible age to be called so. Understanding of its various aspects and relevant intricacies would not only enhance preparedness but also give confidence to tackle eventualities. It has been attempted to include articl

• Language: English
• Publisher: Blue Rose Publishers
• Release date: Apr 18, 2024
• ISBN: 9789362610393

Book preview

HUMAN BODY AND

MEDICAL FIELD

DNA and Gene Expression

Genes are the units of inheritance.

They reside in the genome as sequences of deoxyribonucleic acid (DNA), carrying the information representing a particular polypeptide.

The DNA sequence of the human genome, as well as that of many other species, including mice and rats, has been completely decoded. The human genome contains between 20 000 and 25 000 genes.

The information encoded in the genes is expressed, first by generating a single-stranded messenger RNA (mRNA) identical in sequence to one of the strands of the duplex DNA (RNA transcription), and then by converting the nucleotide sequence of the RNA into the sequence of amino acids comprising a protein (protein translation).

While the protein-coding sequences of genes occupy only about 1% of the entire DNA sequence, their interruption by introns allows them to be spread over huge distances.

Introns, which comprise 24% of the genomic sequence, are non-coding stretches of DNA that are transcribed, but eventually excised from the mRNA, thereby fusing the remaining parts, termed ‘exons,’ by a process called splicing, into the final protein-coding mRNA.

Genes are perpetuated (as in cell division or the generation of gametes) by a duplication process of the double-stranded DNA to give identical copies (DNA replication).

A gene is a stable entity, but can suffer changes in its chemical structure or in its sequence.

Sequence changes are called mutations, and may occur as a result of replication errors or mistakes made during the repair of chemical damage.

The phenotypic results of mutations range from undetectable to lethal.

Patterns of gene expression can undergo changes with time, either in a random fashion, for example, through genomic alterations, or in a programmed manner, as exemplified by the switching on and off of individual genes during development and differentiation.

Ageing is a process of change with time that is associated with 1-increased loss of function, 2- increased pathology, and 3- increased susceptibility to disease.

Although ageing never fails to result in the death of the organism, the information encoded in its genes, is perpetuated in the form of an immortal germ line.

A multitude of physiological, cellular, and molecular changes have been found to occur in ageing individuals of various species.

Changes in genome organization and expression have long been considered as possible explanations for the general breakdown of structure and function during ageing.

Age-related changes in gene expression could occur in a programmed fashion, resulting in phenotypic changes that are similar from cell to cell.

Ageing provides no specific advantage and most researchers now accept that age-related degeneration and death is ultimately due to the greater relative weight placed by natural selection on early survival or reproduction than on maintaining vigour at later ages. This is due to the scarcity of older individuals in natural populations owing to mortality caused by extrinsic hazards, which essentially prevents the manifestation of late age effects of genes. Consequently, such late effects of genes, whether positive or negative, will be ignored by natural selection.

Life span is often considered as the result of a trade-off between growth and reproduction on the one hand and somatic maintenance on the other.

High extrinsic mortality would favour investment of scarce resources in early reproduction rather than somatic maintenance.

Organisms age as a result of the accumulation of unrepaired somatic damage due to their continuous exposure to damageingagents, such as free radicals, the toxic by-products of normal metabolism.

Caloric restriction is a very effective intervention that has been shown to increase life span in multiple species, including mammals.

Cells and the various macromolecular complexes that serve to provide for their function are generally considered as the main target of somatic damage accumulation in ageing.

The maintenance of genomic DNA is of crucial importance to survival because its alteration by mutation is essentially irreversible and has the potential to affect all downstream processes.

Random damage to DNA may affect transcription and result in mutations as a consequence of errors during replication or repair.

Mutations have the potential to result in permanent gene expression changes that are different from cell to cell.

Damage to DNA and other macromolecules in the cell can elicit powerful programmatic responses, such as DNA repair, apoptosis, cellular senescence, and other stress responses.

The gene expression changes associated with these responses would be very similar from cell to cell.

Both stochastic and programmatic changes in DNA and gene expression can be expected to occur during ageing.

Age-related changes in DNA can be expected to be predominantly stochastic. That is, each specific alteration occurs as a relatively rare event, which essentially transforms each organ or tissue into a mosaic of cells.

Each cell would have its unique set of ‘genomic scars’ that distinguishes it from all other cells.

Cellular DNA is continuously damaged by a variety of exogenous and endogenous physical, chemical, and biological agents. Such damage includes breaks in the sugar-phosphate backbone of the DNA, both single-strand breaks and the highly toxic double-strand breaks, base loss, base adducts, methylation, deamination and inter- and intra-chromosomal cross-links.

The main sources of endogenous DNA damage, which is now considered more important than exogenous damage, include hydrolysis and oxidation.

Especially oxidation through reactive oxygen species (ROS), the by-product of oxidative phosphorylation and other normal, physiological processes, can induce a variety of chemical damage into cellular DNA.

Oxidative damage to DNA alone occurs at a rate of 104 hits per cell per day in humans.

Exogenous damage can be a result of exposure to ultraviolet light, background ionizing radiation or environmental chemicals, such as polycyclic aromatic hydrocarbons.

Most of the damage is repaired. However, repair is imperfect, which may lead to an increased steady state level of DNA damage.

Steady state levels of several forms of DNA damage (e.g., breaks, oxidative damage) increase with age in humans.

The mitochondrial genome is much more susceptible to oxidative damage than the overall nuclear genome.

DNA repair efficiencies vary considerably between different types of DNA sequences, with actively transcribed genes being repaired best.

It is not possible to know whether a particular lesion detected today will still be present tomorrow. Hence, the possibility should be considered that any increase in DNA damage, unless it completely overwhelms all defence systems (which at the levels reported is extremely unlikely under normal conditions), has no functional consequences. DNA chemical damage becomes highly relevant when a lesionis fixed in the form of a mutation, that is, when a chemical alteration in DNA structure, recognizable by DNA damage processing systems, is turned into an erroneous base sequence as a permanent part of the genetic heritage.

In contrast to DNA damage, DNA mutations are changes in a DNA sequence that can be transmitted to daughter cells.

Mutations are not altering the DNA chemical structure, but merely its sequence organization. They can affect a gene, gene regulatory region, or some other non-coding part of the genome.

Mutations are usually introduced as a consequence of errors made during replication or repair of a damaged DNA template.

Mutations can vary from point mutations, involving single or very few base pairs, to large deletions, insertions (for example, due to the activity of mobile genetic elements), duplications, and inversions.

In organisms with multiple chromosomes, DNA from one chromosome can be joined to another, and the actual chromosome number can be affected.

Because mutations are rare and do not affect DNA’s chemical structure, they are not easy to detect, and the total number of mutations in individual cells of an aged tissue cannot be quantified.

It has been demonstrated that mutations accumulate with age in most organs and tissues at rates that are tissue specific. A substantial fraction of those mutations, depending upon the tissue, appeared to be genome rearrangements, i.e., deletions, inversions, or translocations.

Similar to DNA damage, the mitochondrial genome accumulates mutations much more rapidly than the nuclear genome. Since there are many copies of mtDNA in each cell, prevention of mutation accumulation may be less urgent in this case.

An important question involves the functional impact of the observed mutation load and its increase with age. For most organs the magnitude of the age-related increase was small, i.e., about twofold on average. However, the functional properties of an ageing organ can become compromised, even if most of the cells still function optimally.

The level of methylation tends to decrease with ageing in most vertebrate tissue.

To summarize, there is abundant evidence for alterations in the DNA of the genome during ageing. The frequency and spectrum of such events may vary from genomic region to genomic region and are also different between tissues.

Defence against the time-dependent loss of DNA functional template takes place at various levels. First, damage can be prevented at an early stage, for example, by the activity of antioxidant enzymes if ROS are the primary cause of the damage. Then, damage can be repaired through the complex system of genome maintenance pathways, restoring the original situation as far as possible. This includes the restoration of methylation patterns and the histone code, which also need to be faithfully propagated during cell division, similar to the DNA primary sequence. Finally, when all other defence systems threaten to be overwhelmed, the cell itself can either shut down its replicational machinery, termed replicative senescence, or be entirely eliminated by programmed cell death or apoptosis. In this sense apoptosis is the ultimate mechanism for the maintenance of phenotypic fidelity in multi cellular organisms.

Naturally, cellular defence systems function well enough at early age. However, as predicted by the evolutionary theory of ageing, there is no reason to assume that the preservation of the genetic material in the somatic tissues until long after the reproductive period has a high priority. It should be noted that cellular defence systems against DNA damage and other stresses can turn from anti-ageing into pro-ageing systems.

Apoptosis and cellular senescence help to suppress cancer at early age, but possibly at the cost of promoting ageing at later ages by exhausting progenitor or stem cell reservoirs.

A powerful response to infection undoubtedly has a high survival value, but may at later age contribute to inflammation.

The combination of suboptimal cellular defence systems and increased age can be expected to give rise to three major cellular endpoints: neoplastic transformation, cell death, and cellular senescence.

The exponential increase in cancer during ageing could be explained in part by increased DNA mutations and/or methylation.

Cell death can be observed as atrophy in a variety of tissue systems in ageing organisms and could be due to increased levels of DNA damage, inducing apoptosis.

Each tissue or cell type has a unique set of active functional modules (groups of proteins that work together to execute a function), the activity of which is primarily determined by transcriptional regulation of the genes involved, with individual genetic, environmental, and lifestyle factors as modifiers.

Random DNA alterations are likely to be tissue specific, possibly as a consequence of tissue function and the tissue-specific utilization of genome maintenance systems.

Gradual accumulation of DNA alterations in an ageing tissue, affecting patterns of gene regulation in a stochastic manner, eventually results in a mosaic of cells, varying from cells that escaped significant damage to cells with severe dysfunctions, neoplastically transformed cells, and cells that are dying.

Ageing has been considered both as a programmed series of events and a stochastic process of damage accumulation.

The evolutionary theory of ageing is a logical explanation of senescent deterioration and death and excludes a genetic program that actively causes ageing as a purposeful process.

Ageing has programmatic aspects.

Each chromosome is viewed as a complex information organelle with sophisticated maintenance and control systems.

Each part has a function, even its non-protein-coding parts. Such a holistic view of the genome would assign a variety of functions to non-coding DNA (e.g., structural maintenance, gene regulation).

The single most striking characteristic of mammalian genomes is: redundancy of genetic information.

The simplest form of redundancy is copy number. With many gene copies present, the effect of some loss has no immediate adverse effects. This could explain, for example, the increased accumulation of DNA damage and mutations in mtDNA, which has ample redundancy to compensate for such loss of undamaged DNA template. Other forms of redundancy include the fact that more than one genosgenos may specify a given cellular function. Finally, the existence of metabolic and other cellular networks allows the cell to accomplish similar endpoints through multiple overlapping pathways.

A more useful background for understanding ageing would be in terms of a gradual loss of functional informational redundancy. Rather than the inactivation of unique genes with unique functions, one should think of an initially tolerable loss of genome structural integrity, which would become manifest as a loss of phenotypic flexibility.

Rather than some form of massive loss of essential genes, it is more likely that ageing is accompanied by a slow but inexorable loss of genetic redundancy. This lead to subtle scattered changes in gene expression and in the efficiency of gene regulation. Although primarily a stochastic process, this would rapidly take on some programmatic characteristics.

The continuous randomization of the genome, by alterations in genes or in regions important in their regulation, unequivocally triggers the cell to respond. This response is programmatic and consists of species-specific stress and repair systems.

DNA damage as the original driver of a universal process of ageing has some inherent logic.

Genetic damage essentially prevents the perpetuation of life, since it interferes with replication (and transcription); an opportunity, because it allows the generation of genetic variation through errors in replicating a damaged template, thereby facilitating evolutionary change.

Genetic stability in somatic cells of metazoa has become part of the trade-off between the allocation of scarce resources to either reproduction or somatic maintenance and is not expected to be maximized.

While the concept of DNA damage as a main driver of ageing is intuitively attractive, evolutionary logic dictates that other causes of ageing would emerge over evolutionary time.

Genetics

Genetics as a research tool has allowed the identification and reading of the common thread uniting all life on earth, the DNA molecule.

Genetics as a discipline has united the biological and biomedical sciences by providing a common framework and tool kit for exploring the multiple processes of life and by providing a common terminology that allows researchers in numerous disparate fields to share information through the identification of genes and the interpretation of their DNA sequence.

Genetics refers to the underlying genetic elements making up living species as well as to the discipline that analyzes these processes.

Genetic studies of ageing in humans have proceeded through several distinct routes. First has been the study of an in vitro model of ageing: the limited number of cell divisions observed in most, if not all, non-transformed cells in culture, which we will call cellular senescence.

Second has been the study of rare diseases that have been termed segmental progeroid diseases to suggest that in each of these diseases many, but not all, aspects of ageing have been accelerated. Examples of these include Hutchinson- Gilford disease and Werner’s syndrome.

Third, both pedigree analysis and population studies have begun; this work may ultimately reveal genes or, at least chromosomal regions, that are associated with various human diseases and with alterations in length of life.

Finally, twin studies and other designs have recently been used to begin to determine what proportion of the variation in age-related function or age at death is genetically determined.

Some 35 years ago it was recognized that human cells could not go on dividing forever in tissue culture. This revolutionary observation, cellular senescence, countered classical observation by giants in the field. The acceptance of this fact was quickly followed by the suggestion that the finite proliferative capacity of tissue culture cells might be a model for, or even the basis of, normal human ageing.

The 1970s saw careful characterization of the ageing phenotype of these cells and the finding that the proliferative capacity of these cells declines in parallel with the age of the donor. This fact together with the observations that cell lines derived from certain ‘segmental progeroid diseases’ have more limited proliferative potential and that proliferative potential correlates with the maximum life span potential of a species, have led many to accept that cellular senescence is a valid model of human ageing. More recent evidence seems to suggest that cellular senescence may well be cellular differentiation; many similarities between cellular senescence, as studied in the fibroblast, and muscle cell differentiation can be made. Although the dispute cannot be resolved at this time, it seems likely that cellular senescence is a model for terminal differentiation and has relevance to some in vivo cellular ageing phenomena.

The analysis of human tissue culture cells is much easier than is the study of intact organisms, and the study of these cells has allowed significant advances in our understanding of cellular processes. The genes responsible for cellular senescence are being identified, and their role in limiting the proliferative capacity of these cells is being elucidated. A surprising result of genetic studies is that in immortalized cell lines, the immortal phenotype is recessive (i.e., a lack of some essential protein is probably responsible for immortalization rather than the converse).

Immortalization seems to result from mutation of any one of four complementation groups; three of these groups have been localized to individual chromosomes.

A second process has also been tentatively identified as a determinant of cellular senescence: the limited proliferative capacity of the telomeres (chromosome ends).

The telomere model states that, in the absence of telomerase, telomeres continue to shorten until chromosome instability and other problems occur. Most, perhaps all, human tumours have reactivated the telomerase allowing indefinite replication. It could be that the absence of telomerase in normal somatic cells is an additional assurance preventing oncogenesis and tumour formation.

Generally, mutations are deleterious because they eliminate or modify functional DNA sequences leading to an alteration at the protein level; thus, it is expected that mutations should shorten the life span.

In an effort to find human gerontogenes, a number of marker association studies have been undertaken. In these studies longevity is shown to be associated with certain alleles and genes within small regions of the human genome by characterizing genetic markers at certain candidate loci.

The HLA locus has long been a candidate for determining human longevity and at least two studies have suggested that certain HLA haplotypes may be associated with increased longevity in at least some populations. ACE and APOE have been tested as candidates and both have been found to be associated, although not consistently in the direction predicted.

The best studied, age-related genetic disease in humans is AD. About 2–6% of people over 65 show symptoms of AD; the prevalence of this disease increases strikingly with age, such that by 85 as many as 40% of the population may show symptoms of AD. Pedigree analysis has allowed the localization of three distinct genes that are involved in the specification of familial AD (FAD). Rare mutations in the gene encoding the precursor protein of Alzheimer associated amyloid on chromosome 21 are associated with FAD, but these account for only 2–3% of the affected individuals. Genes on 14 and 19 are susceptibility loci associated with late-onset (after age 65) and early-onset forms of the disease, respectively. There are still other pedigrees in which the susceptibility to FAD is unlinked to these three loci, which suggests that there are still other loci to be found. Thus FAD is clearly very heterogeneous in origin. A further complication is that the degree to which FAD is genetic is uncertain, with estimates ranging from 10–100%. A marked association with the APOE locus on chromosome 14 has been shown and replicated in many studies, such that individuals homozygous for APOE-e4 have an almost eightfold increase in the probability of getting AD at almost any age when compared with people carrying other alleles of APOE

From analysis of parent–offspring correlations in life span and differential life spans of identical and fraternal twins, estimates of the fraction of the variation in life span that is under genetic control (the heritability) can be made. Human heritability studies suggest modest amounts of inheritance of longevity, perhaps on the order of 10–30%. Longitudinal studies of various traits suggest that the heritable proportion may change with age in rather surprising ways.

Early studies largely focused on proving that genes play a role in determining longevity or rate of ageing and on quantitative estimates of this genetic component through estimations of heritability.

Studies have shown significant genetic components for longevity in mice, in fruit flies, and in the nematode. Typical heritability estimates are in the range of 15–30%. These studies also clearly demonstrate that many genes affect this variation in life span.

Longer life is associated with reduced ovary weight early in life and increased resistance to starvation, desiccation, and other environmental stresses. Indeed, selection for increased desiccation resistance yields longer-lived lines. These responses result from the action of many (even hundreds) of genes or QTLs. Attempts to dissect the process further have revealed regions of the genome that may be especially rich in QTLs, but further dissection has met with little success, perhaps because so many QTLs are involved. Generally, the results are consistent with a trade-off between early fertility and extended life span as might be predicted by the evolutionary theory of ageing. However, these are not critical tests of the theory because so many genes are being selected for simultaneously and thus the trade off may not be at the level of the individual gene.

The long-lived strains were also resistant to a variety of environmental stresses including free radicals. Indeed at least two different groups have suggested that the physiological basis of the extended life is increased resistance to reactive oxygen species. A variety of other specific physiological alterations have been implicated in these long-lived strains, but none of these alternative models have been critically tested in these selected lines. At least one attempt to critically test the involvement of superoxide dismutase (SOD) in extended life resulted in a failure to detect a significant effect, but this finding was dismissed post hoc because this locus represented only one of hundreds of genes that were segregating in the population. This apparent lack of ability to refute this model suggests that selective breeding for increased life span in Drosophila is not likely to yield additional relevant insights into the molecular and physiological basis of life extension; for that other approaches are needed, as described next.

Our lab has discovered that most, if not all, long lived mutants of the nematode are more resistant to many environmental stresses. The bases for this statement are twofold. First, four of the long-lived mutants (age-1, daf-2, daf-28, and spe-26) are more resistant to two distinct stressors (thermal stress and UV irradiation). Only age-1 has been shown to be resistant to reactive oxygen species; the clk-1 mutation has not been tested for any stressors. Second, induction of thermotolerence via non-lethal heat stress results in a longer life span. age-1 mutants have higher levels of Cu-Zn SOD and catalase at later ages. age-1 mutants also respond to thermal stress by expressing heat shock protein 16 (HSP-16), a crystalline homolog, at higher levels than does the wild type. Thus, the age-1 mutation may be uncovering a common genetic pathway that is involved in the mediation of stress response from a variety of environmental stresses.

The ultimate demonstration that a particular process is affected by a particular gene is to show that altering a single gene affects that particular process. The best way to demonstrate this causality is to alter a particular gene and to demonstrate that this affects the phenotype of interest, for instance, life span. Exactly this approach is used in the analysis of transgenic animals (mice, yeast, fruit flies, and nematodes) to demonstrate an effect on ageing as a result of alterations in one or a few genes. This approach is just beginning to be applied to a variety of systems to test specific genes for their effects on life span and/or rate of ageing.

The best example of the use of transgenics is in Drosophila, where transgenic strains that overexpress both Cu-Zn SOD and catalase by 20–50% have been constructed. These transgenic strains had longer life spans and lower rates of mortality than did the wild type. There was also a decrease in the rate of accumulation of oxidized protein and a delay in loss of physical performance. It should be noted that transgenics for both SOD and catalase had life extensions that were much better than the sum of the two single transgenic strains alone. This might be suggested by the involvement of catalase in detoxifying the hydrogen peroxide radical produced by Cu-Zn SOD.

Homeostasis, Homeodynamics and Ageing

All living systems, in contrast to the non-living systems, have the intrinsic ability to respond, counteract, and adapt to the external and internal sources of disturbance.

The traditional conceptual model to describe this property is homeostasis, which has dominated biology, physiology, and medicine since the 1930s.

Since the 1990s, the term homeodynamics, introduced by F. E. Yates in 1994, has been increasingly used – though it has not yet fully succeeded in replacing homeostasis.

The concept of homeodynamics accounts for the fact that the internal milieu of complex biological systems is not permanently fixed, is not at equilibrium, and is a dynamic regulation and interaction among various levels of organization.

Almost in parallel with the development of the concept of homeodynamics, the term allostasis, coined and introduced by Peter Sterling and J. Eyer in 1988, has been gaining recognition and use.

According to the allostasis model, stability through change is the most realistic situation for living biological systems. The allostasis model also takes into account characteristics such as reciprocal tradeoffs between various cells, tissues, and organs, accommodative sensing and prediction with respect to the severity of a potential stressor, and the final cost of making a response and readjustment to bring about the necessary change.

Every act of allostasis adds to the allostatic load in terms of, for example, unrepaired molecular damage, reduced energy deposits, and progressively less efficient or less stable structural and functional components.

Ageing, senescence, and death are the final manifestations of unsuccessful homeodynamics or failure of allostasis.

Of the numerous biochemical and physiological pathways and processes operating in cells, tissues, organs, and systems in any organism, the key pathways and processes that can be considered to be quintessential components of the homeodynamic machinery are the following:

1. The multiple pathways of nuclear and mitochondrial DNA repair, including those for maintaining the accuracy of the information transfer from DNA to RNA to proteins and those for the removal of spontaneous lesions in DNA.

2. The processes for sensing and responding to intra and extracellular stressors, such as heat shock response, hemeoxygenase response, stress hormones, and ionic fluxes.

3. The pathways for protein repair, such as the renaturation of proteins by chaperones, and the enzymic reversal of the oxidization of amino acids.

4. The pathways for the removal and turnover of defective proteins by proteasomes and lysosomes.

5. The antioxidative and enzymic defences against reactive oxygen species.

6. The processes for the detoxification of harmful chemicals in the diet.

7. The cellular and humeral immune responses against pathogens and parasites, including massive apoptosis (programmed cell death) after the completion of the cellular immune response.

8. The processes of wound healing, blood clotting, and tissue/organ regeneration.

In addition to these main categories of pathways and processes comprising the homeodynamic machinery, some other physiological processes include temperature control, the epigenetic stability of differentiated cells, and fat storage and energy utilization. Of course, all these processes involve genes whose gene products and their interactions give rise to a homeodynamic space, which is the ultimate determinant of an individual’s chance and ability to survive and maintain a healthy state.

At present, our knowledge about the number of genes and their variants and their multiple interactions and consequences is too meagre to identify, define, and manipulate the homeodynamic machinery in any sensible way. In the case of human beings and other social animals, determining the role of psychosocial factors as integral components of the homeodynamic machinery is one of the biggest challenges.

Why members of different species have different life spans and what determines the life span potential of an organism are challenging evolutionary questions. The natural life span of a species has also been termed essential life span (ELS), or the warranty period of a species. ELS is defined as the time required to fulfil the Darwinian purpose of life, that is, successful reproduction for the continuation of generations.

Species undergoing fast maturation and early onset of reproduction with large reproductive potential generally have a short ELS. In contrast, slow maturation, late onset of reproduction, and small reproductive potential of a species is concurrent with its long ELS.

For example, the ELS of Drosophila is less than 1 week as compared with the ELS of Homo sapiens of less than 50 years, even though in protected environments (laboratories and modern societies), a large proportion of populations of both species can and do live for much longer than that.

Based on the allocation of energy and metabolic resources (EMR), available EMR must be divided among three fundamental features of life: (1) basic metabolism, which includes biochemical synthesis, respiration, cell turnover, movement, feeding, digestion, and excretion; (2) reproduction; and (3) maintenance through homeodynamic machinery

Whereas basic metabolism is essential for all animals, the extent of investment in reproduction and maintenance can vary between species. This is the trade-off, known as the disposable soma theory of ageing, between investment in maintenance and investment in reproduction, which are related inversely. The evolved balance between the two depends on the life history strategy and ecological niche of the species. Several comparative studies have reported positive correlations between life span and the ability to repair DNA, detoxify reactive oxygen molecules, respond to and counteract stress, and replace worn-out cells. In addition, negative correlation has been demonstrated between longevity and the rate of damage accumulation, including mutations, epimutations, macromolecular oxidation, and aggregation of metabolic by-products.

Although the reasons for the longevity differences among the species can be explained by the disposable soma theory, significant differences among individuals within a species are much harder to explain.

Genes, milieu (environment), and chance factors are thought to be the determinants of individual life span.

Of these factors, some understanding is emerging about genes and their associations with survival and longevity.

In human beings, association studies on gene polymorphism and longevity have identified numerous genes that function in a variety of biochemical pathways, such as cytokines, cholesterol metabolism, DNA repair, and heat shock response. Such studies will ultimately lead to the elucidation of the nature and number of genes involved in comprising the homeodynamic space of an individual, which may be the basis for its modulation and intervention.

The evolved nature of the homeodynamic machinery, in accordance with the life history traits of different species, sets an intrinsic genetic limit on the ELS. Therefore, ageing is considered as an emergent phenomenon seen primarily in protected environments that allow survival beyond the natural life span in the wild. No real genes for ageing (gerontogenes) are thought to exist, and the genes in ageing were defined as being virtual gerontogenes owing to their indirect effects on ageing and longevity.

Based on a large body of descriptive data, ageing has been defined as the progressive failure of homeodynamics.

Collectively, biogerontological data characterize ageing as a progressive accumulation of molecular damage in nucleic acids, proteins, and lipids. Since the occurrence and accumulation of molecular damage are mainly stochastic, ageing is manifested differently in different species, in individuals within a species, organs, tissues, cells, and subcellular components within an individual.

The main cause of age-related accumulation of molecular damage and its consequences is the inefficiency and failure of maintenance, repair, and turnover pathways that constitute the genetically determined homeodynamic machinery.

The main examples of such hypotheses include altered gene regulation, somatic mutation accumulation, protein errors and modifications, reactive oxygen species and free radicals, immune remodelling, and neuroendocrine dysfunctioning. At the cellular level, the so-called telomere loss theory and the epimutation theory of progressive loss of DNA methylation are other examples of mechanistic explanations for the loss of proliferative potential of normal, differentiated, and diploid cells in vitro and in vivo.

According to the homeodynamics-based explanations for ageing and longevity, the occurrence of ageing in the period beyond ELS, and the onset of one or more diseases before eventual death appear to be the normal sequence of events. This viewpoint makes modulation of ageing different from the treatment of one or more specific diseases. In the case of a disease, such as a cancer of any specific kind, its therapy will, ideally, mean the removal and elimination of the cancer cells and restoration of the affected organ or tissue to its original, disease-free state. What, then, will be the treatment of ageing and to what original age-free stage would one hope to be restored?

Considering ageing as a disease and then trying to cure that disease is unscientific and misguided. Similarly, although piecemeal replacement of non-functional or half-functional body parts with natural or synthetic parts made of more durable material may provide a temporary solution to the problems of age-related impairments, it does not modulate the underlying ageing process as such.

Scientific and rational anti-ageing strategies aim to slow down ageing, to prevent and/or delay the physiological decline, and to regain lost functional abilities. Strengthening, improving, or enlarging the homeodynamic space at the level of all genes comprising the homeodynamic machinery of an individual may be the ideal anti-ageing solution. However, such a gene therapy approach for gerontomodulation requires redesigning the blueprint for structural and functional units of the body at the level of genes, gene products, macromolecular interactions, molecular milieu interactions, and so on.

Considering how little information and knowledge we have at present about the interacting variants of genes, molecules, milieu, and chance, it is not clear what this approach means in practical and achievable terms. Improving the milieu in which the homeodynamic machinery operates is the other strategy that is being followed by most of the so-called anti-ageing experts. Some of the main approaches include supplementation with hormones including growth hormone, dehydroepiandrosterone (DHEA), melatonin, and estrogen, and nutritional supplementation with synthetic and natural antioxidants in purified form or in extracts prepared from plant and animal sources.

Although certain of these approaches have been shown to have clinical benefit in the treatment of some diseases in the elderly, none really modulate the ageing process itself. Furthermore, claims for the benefits of intake of high doses of vitamins and various antioxidants and their supposed anti-ageing and life prolonging effects have very little scientific evidence to back them.

In contrast, nutritional modulation through caloric restriction (CR) has been shown to be an effective anti-ageing and longevity-extending approach in rodents and monkeys, with possible applications to human beings. However, this is a highly debatable issue at present both in terms of the practicalities of defining CR and in terms of applying CR to human beings in physiological and evolutionary contexts.

In a more realistic and near-future scenario, a promising approach in ageing intervention and prevention is based on making use of an organism’s intrinsic homeodynamic property of self-maintenance and repair.

Since ageing is characterized by a decrease in adaptive abilities due to progressive failure of homeodynamics, it has been hypothesized that if cells and organisms are exposed to brief periods of stress so that their stress response-induced gene expression is up regulated and the related pathways of maintenance and repair are stimulated, one should observe anti-ageing and longevity-promoting effects.

Such a phenomenon, in which stimulatory responses to low doses of otherwise harmful conditions improve health and enhance life span, is known as hormesis.

The paradigm of hormesis in ageing is moderate exercise, which is well known to have numerous beneficial effects despite or because of it being a generator of free radicals, acids, and other damageing effects.

Mild stresses that have been reported to delay ageing and prolong longevity in various systems include temperature shock, irradiation (UV, gamma, and X-rays), heavy metals, pro-oxidants, acetaldehyde, alcohols, hyper gravity, exercise, and food restriction.

Hormesis-like beneficial effects of chronic but mild undernutrition have been reported for human beings.

Intermittent fasting has been reported to have beneficial effects on glucose metabolism and neuronal resistance to injury.

Although at present there are only a few studies performed that utilize mild stress as a modulator of ageing and longevity, hormesis can be a useful experimental approach in biogerontology. However, there are several issues that remain to be resolved before mild stress can be used as a tool to modulate ageing and prevent the onset of age-related impairments and pathologies by improving the homeodynamic space of an individual.

Some of the issues in the applicability of hormesis as a homeodynamic stimulator are the following:

1. establishing biochemical and molecular criteria for determining the hormetic levels of different stresses;

2. identifying differences and similarities in stress response pathways initiated by different stressors;

3. quantifying the extent of various stress responses;

4. determining the interactive and pleiotropic effects of various stress response pathways;

5. adjusting the levels of mild stress for age-related changes in the sensitivity to stress;

6. determining the biological and evolutionary costs of repeated exposure to stress; and

7. determining the biological significance of relatively small hormetic effects, which may or may not have large beneficial effects during the entire life span.

Two of the main lifestyle interventions, exercise and reduced food intake, both of which bring their beneficial and antiageing effects through hormesis, are being widely recognized and increasingly practiced as an effective means of achieving a healthy old age.

In the consideration of irradiation as a hormetic agent, epidemiological studies of the public, medical cohorts, and occupational workers confirm that low doses of radiation are associated with reduced mortality from all causes, decreased cancer mortality, and reduced mutation load observed in ageing and cancer. Increasing use of low-dose total body irradiation as an immunotherapy for cancer also has its basis in hormesis. However, in order that this approach could be developed into a safe and preventive strategy against a variety of age-related diseases, certain issues, for example, those related to radiation load versus mortality curve, bystander effects, and the nature of energetic particles, need to be resolved.

Hormesis through mental challenge and through mind-concentrating meditational techniques may be useful in stimulating inter- and intracellular debris removal processes, thus preventing the neuronal loss that leads to the onset of age-relatedneurodegenerative diseases.

One can also expect the availability of certain nutriceutical and pharmacological hermetic agents to mimic mild stress as a challenge for the homeodynamic machinery.

Plant components such as resveratrol, celastrol, and curcumin are among the potential hormetic molecules identified so far.

Living systems survive by virtue of a set of defensive maintenance and repair systems that comprise their homeodynamic ability. A large number of interacting genes and genetic networks constitute this machinery, the exact details of which are yet to be unraveled. Successful homeodynamics is crucial for the growth, development, and maturation of an organism until the reproduction and continuation of generations are assured. Homeodynamics is thus a longevity assurance mechanism, whose strength, efficiency, and range have evolved in accordance with the evolutionary history of the species. Survival beyond the required essential life span of a species is necessarily accompanied by the progressive accumulation of random molecular damage.

The progressive failure of homeodynamics leads to the physiological malfunctioning manifested as a general functional decline, diseases, and ultimate death.

Rational strategies to slow down ageing or to prevent the onset of age-related frailty and diseases require the stimulating and strengthening of the homeodynamics of individuals.

Behavioural Genetics

The age-related diseases and physiological changes that we have come to think of as part of ‘normal ageing’ do not affect all people in the same way, nor do all individuals experience the same changes as they age. In fact, older adults are thought to be more diverse than younger adults in health, psychological functioning, and dimensions of social interaction.

The observed heterogeneity among age peers increases over the life course, and the members of a cohort are said to ‘fan out’ as they age, becoming more dissimilar for any given characteristic

Research shows that the relationship among family members for longevity is modest and what children inherit from their parents is not longevity per se, but rather ‘frailty That is, children inherit susceptibility to disease, or other risk factors that contribute to their chances of death at different ages

Estimates of the heritability of frailty have consistently been around 50%, suggesting that hereditary predispositions may influence the risk of death at different ages, rather than directly determining age at death

The risk of death from myocardial infarction (heart attack) is one and a half to two times greater in a man whose male sibling died at an early age (less than 50 years of age). This type of premature CHD is a single gene defect, affecting lipoprotein metabolism, which accounts for about 5% of coronary disease in the population

In the young cohort (age <65) the heritability estimate for total cholesterol was 63%, whereas in the older group (age > 65) the heritability was 26%. Although hereditary factors are clearly important, genetic influences appear to be more pronounced at younger ages. Shared rearing environment also contributed to individual differences in total cholesterol levels (especially in the older cohort), accounting for 16 and 36% of the variance in the young and old cohort, respectively

Research regarding patterns of similarity for male twins suggest that the familial aggregation of cardiovascular disease results from a heritability of 60% for blood pressure (both systolic and diastolic), 25% for hematocrit , 53% for uric acid, and 56% for triglyceride levels.

‘Healthy ageing’ (primarily defined as the absence of cardiovascular disease up to age 70) is under a significant degree of genetic influence, with estimates hovering around 50%.

Genetic factors increase the risk of stroke but that the effect is moderate.

Close relatives of patients with diabetes mellitus (DM) have increased risk of developing the disease, but the risk is almost exclusively for the same form of the disorder (insulin or non-insulin DM) as is present in the pro band. Heritability appears stronger for non-insulin (type II) diabetes.

Results suggest that interventions directed toward unique aspects of the environment (e.g., diet, nutrition, health-care utilization, stress maintenance) may be especially important in lengthening the period of active life and contributing to positive outcomes in later life.

For many aspects of health and longevity, results of behavioural genetic research indicate that Similarities between parents and offspring are typically lower than resemblance between siblings within a family, suggesting that cohort or age is important to consider.

It is also likely that apparent differences in heritability across the life span are due to selection effects on longevity or functional capacity.

Genetic influences may appear to be more important for health in middle adulthood.

Cognitive abilities are among the most heritable dimensions of behaviour, with genetic factors consistently accounting for about 50% of the variability in studies of childhood, adolescence, and young adulthood. Studies of later life have indicated higher levels of heritability for general cognitive abilities than are typically observed in younger populations

Research on specific cognitive abilities (e.g., verbal, perceptual speed, spatial orientation, memory) also implicates substantial genetic involvement, albeit less than what is reported for general abilities. Across multiple studies, the heritability’s range from 0.0 to 0.86, with the lowest estimates for measures of memory and the highest estimates for verbal ability and perceptual speed.

Genetic influences on the cognitive domain are more general than specific.

Research shows that more a trait taps into general cognitive ability, the more heritable it is.

Results of study indicates early family environment, both shared and uniquely experienced, impacted familial similarity in adult cognitive functioning, especially in siblings

Studies shows that Genetic influences on memory are largely mediated by processing speed and social class, whereas environmental influences on memory are mediated to some extent by physical activity. Thus, the authors suggested that interventions for a decline in memory functioning might best be targeted at lifestyle variables such as physical activity.

Results of research in childhood, adolescence, and young adulthood indicate that genetic influence for self-reported personality is significant, but moderate, ranging from 30 to 50%. Although environmental influence is important, almost all the environmental variance is non-shared. Nonetheless, most of the variance is environmental, even for the most heritable personality traits. Further, heritability for personality in later adulthood is only slightly lower than results reported earlier in the life span.

Relatively speaking, environmental influences are more important at each time point, but are less stable from time to time, whereas genetic effects are stable, but are of slightly less importance. Thus, although measures of personality are moderately heritable, the genetic effects over time appear to be consistent, contributing to continuity and not change

Behavioural genetic research has also assessed characteristics of personality that may be particularly relevant in later life One example is locus of control, which has been associated with both physical health and psychological well-being. It is observed that genetic influences are most important for self-attributions concerning responsibility and life direction, accounting for 30% of the variance.The familial similarity for the perceived role of luck in determining life’s outcomes, however, is largely due to shared rearing environmental influences. Similar results were found regarding genetic and environmental influences on health control beliefs (i.e., due to internal control, chance, or powerful others) and the relationship with depression, life satisfaction, and indices of health in the oldest old.

Dementia is a global term for any neurological disorder whose primary symptomology is the deterioration of mental functioning. Alzheimer’s disease (AD) is arguably the most severe and devastating of all of the different types of dementia, accounting for about 50% of all cases of severe dementia.

Many epidemiological studies have been carried out in order to identify risk factors for AD. Apart from increased age, the other variable that has been consistently identified is a family history of the disorder. first-degree relatives of individuals with AD have more than double the risk of also developing AD.

Depression in older adults is extremely common: perhaps as many as one-third of older adults are clinically depressed. Research is not yet sufficient to draw clear conclusions about the extent of genetic influence on depression throughout the life span; however, a meta-analysis of major depression using data from family, adoption, and twin studies estimated heritability at 37%, with the remaining variance due to unique environmental factors.

There is some evidence, however, that genetic factors might increase in importance after 60 years of age, perhaps due to genetic influences on frailty or vitality

Several large family studies have indicated a familial resemblance for depression.The morbidity risk for depression was about 25% for first-degree relatives of depressed pro bands as compared to about 10% in the population.

The frequency of stressful life events was greater among the relatives of depressives than in the general population, even when negative events associated with the pro bands were discounted. These results suggest that both the liability for depression and the propensity to experience stressful life events are familial.

Life events happen (or are perceived to happen) to some people more than others.

Negative life events may be genetically influence by attributes of individuals and that events of the type traditionally reported do not just happen capriciously.Controllable life events, which may be related to aspects of an individual’s personality or mood state, should be more heritable than uncontrollable one.

As predicted, controllable events showed greater genetic influence.

Genetically influenced characteristics such as personality may affect how individuals construct their social environments and how they feel about and behave toward others. In addition, others may respond to individuals on the basis of genetically influenced characteristics. It is also possible that genetic influences are detected because most of these measures rely on self-reported perceptions of the environment, and genetic effects could accrue because these perceptions filter through a person’s memories, feelings, and personality.

Studies on measures of social support and psychological well-being in later life shows that both genetic and environmental influences are important in the etiology of this relationship. The genetic influences that contribute to the perceived adequacy of the support network also contribute to depressive symptoms and life satisfaction. Non-shared environ mental influences also mediate this phenotypic relationship.

Environmental(shared and non-shared) influence the developmental interface between nature and nurture and the etiology of age-to age continuity and change.

Genetic influences are likely to be significant and substantial for many dimensions of variability in later life.

Bioenergetics

Bioenergetics is a broad subject covering all aspects of energy metabolism, from the biochemical and cellular level to the whole animal.

The ageing process is associated with changes in nearly all aspects of bioenergetics. Ageing is associated with decreases in both energy intake and energy expenditure. These changes contribute to an age-related shift in body composition toward a decrease in lean body mass (LBM) and an increase in percent body fat. These age-related changes in energy metabolism place older individuals at greater risk for detrimental weight loss when faced with injury or disease. Experimental manipulations of components of energy metabolism have also been shown to have dramatic effects on life span and physiological parameters.

Specifically, dietary calorie restriction is the only intervention that has consistently been shown to increase maximum life span in mammalian species, while increased energy expenditure through physical activity slows the decline in some physiological parameters with ageing. Thus, bioenergetics appears to play a central role in the ageing process.

Dietary calorie restriction has consistently been shown to extend life span and decrease or delay the development of physiological impairments and diseases associated with ageing. This retardation of ageing by calorie restriction suggests a link between energy metabolism and the fundamental mechanisms of ageing. Changes in many aspects of energy metabolism are among the most consistent and noticeable characteristics of ageing. These changes in energy metabolism may contribute to physical impairments and disease.

Ageing is often associated with shifts in energy balance, with obesity being a particular problem in midlife and wastline a problem for many who survive to advanced age. Changes in body weight (BW) and body composition are a function of total body energy balance (the difference between energy intake and energy expenditure). BW loss is accomplished by a negative energy balance. The factors in the energy balance equation, therefore, are energy intake, energy storage, and energy expenditure.

Energy intake is simply the caloric content of the food eaten by the individual. Energy consumption is a function of the total amount of diet consumed and the chemical composition of the diet. Energy intake is controlled by both psychological and physiological factors. Energy intake declines with advancing age.

Energy storage refers to the chemical form in which excess energy is stored in the body. Excess energy may be stored as fat, protein, or carbohydrates. The majority of the body’s energy is stored either as fat (which contains the most calories per gram of tissue) in adipose tissue or as protein in muscle, with limited amounts stored as carbohydrates in the form of glycogen.

Ageing is associated with a decrease in LBM (muscle). During middle age, fat mass increases, while with advanced age body mass tends to decrease due to loss of both lean and fat mass.

Energy expenditure is the final component of energy balance. Energy expenditure is composed of four parts: basal metabolic rate (BMR) or resting energy expenditure, the thermic effect of meals (TEM), physical activity, and thermogenesis (i.e., energy expenditure required for maintenance of body temperature).

BMR is defined as the measurement of resting, post absorptive energy expenditure in individuals at thermoneutrality; it is typically responsible for 50–80% of total energy expenditure. BMR represents the energy cost of cellular ‘maintenance’ processes, such as Naþ/Kþ-ATPase activity, mitochondrial proton leak, protein turnover, ionic calcium movements, triacylglycerol turnover, and other substrate cycles.

TEM describes the energy expenditure associated with the digestion, absorption, and assimilation of food. TEM is responsible for approximately 10% of total energy expenditure but will vary depending on meal size and composition.

Physical activity is the most variable component of total energy expenditure and is typically responsible for 10–40% of total energy expenditure. Physical activity is the energy expenditure associated with muscular movement (beyond muscular activity that typically occurs in the resting state).

Thermo genesis is the component of total energy expenditure that represents heat production for the maintenance of normal body temperature. This is typically a minor contributor to energy expenditure in individuals that are not undergoing significant thermal stress.

Ageing tends to result in a decrease in all of the components of energy expenditure. Age-related decreases in BMR, physical activity, and total energy expenditure have been reported in multiple studies.

The exact effect of age on TEM is not clear, with studies reporting either a decrease or no change in TEM with ageing.

Ageing is generally associated with a decrease in energy intake, which has the potential to cause several problems. First, a decrease in energy intake is often not matched with a proportionate change in energy expenditure, which can lead to negative energy balance and loss of body mass. This can be extremely damageing to an individual already with a compromised body composition and lead to an increased risk of morbidity and mortality. Second, a decrease in energy intake is usually associated with a decreased intake of other nutrients, resulting in increased risk of malnutrition-related illnesses. Several studies have shown that a significant portion of the elderly population is deficient in at least one major nutrient. Matching energy intake to energy expenditure is clearly an important concern in the elderly.

Decreases in energy intake may be associated with several other changes that occur with the ageing process.

Impairment of taste and smell sensation occurs with increasing age; however, the impact of these changes on energy intake is not clear. Depression and some forms of medication are common causes of decreased appetite and food intake in the elderly. Problems with oral health, poor dentition, and gum disease also contribute to decreased food intake in some elderly people. Additionally, ageing is associated with decreased saliva production and swallowing problems that can make eating difficult for some individuals. Several studies have demonstrated that ageing is associated with an impairment in the regulation of food intake that prevents appropriate compensation for periods of either under- or over-feeding. For example, young individuals typically follow a period of decreased energy intake with a compensatory increase in food intake to make up for the energy deficit, while several studies have shown that older individuals do not show this response.

Ageing has been associated with a decrease in factors that control short term regulation of energy intake (i.e., stimuli that determine meal length). In a few studies, ageing has been shown to decrease the number of opioid receptors, reduce opioid stimulation of food intake, decrease gastric fundal compliance and increase antral stretch, and slow the rate of passage through the gastrointestinal tract. Several studies have also reported that ageing is associated with increases in circulating cholecystokinin (CCK) levels and sensitivity to CCK.

In experiments, total food intake is not altered by administration of short-term food intake inhibitors, presumably because the decrease in meal energy intake is compensated by increased meal frequency. Therefore, it is likely that the decreases in food intake with ageing are primarily due to alterations in ‘long-term’ regulators of energy intake. Energy intake is controlled through a complex interaction of hormones (i.e., leptin and ghrelin) and neuropeptides located in the hypothalamus and other brain regions.

While ageing does not consistently increase serum leptin levels, it has been proposed that alterations in leptin sensitivity may play a role in age-related decreases in energy intake. Ghrelin levels have been reported to increase with ageing, and it appears that this hormone does not play a major role in decreasing food intake with ageing. In the hypothalamus, ageing is associated with decreased sensitivity and/or decreased levels of neuropeptide Y (NPY). It appears that decreased NPY stimulation of feeding occurs in later life and contributes to age-related decreases in energy intake.

Studies have also reported that ageing is associated with a decrease in the hypothalamic levels of agouti related peptide (AGRP) and orexin (both stimulators of food intake) and an increase in levels of cocaine and- amfetamine-regulated transcript (CART, an inhibitor of food intake). Levels of circulating cytokines are also commonly increased in the elderly, and it is possible that they could contribute to alterations in energy intake with ageing. Thus, there is evidence to indicate that neuropeptides such as NPY, AGRP, CART, and orexin may be involved in age-related decreases in food intake.

It is thus likely that multiple factors contribute to age related decreases in energy intake.

Ageing is associated with very clear changes in body composition. In general, ageing results in a decrease in total body mass along with a decrease in LBM and total body protein while increasing percent body fat.

Progressive loss of body protein due to a large decline in skeletal muscle mass (sarcopenia) is a well-established component of the ageing process. There is evidence that muscle mass declines by up to 7% per decade between early adulthood and old age. The changes in body protein with ageing are primarily a function of decreases in skeletal muscle mass, because non-muscle LBM (internal organs) often shows only slight decreases with ageing. This reduction in skeletal muscle mass decreases the overall motor function of the muscles and may limit the individual’s ability to respond to stresses requiring mobilization of body protein stores. Although only a slight decrease in non-muscle LBM has been reported, these changes should not be ignored and may be extremely important since the internal organs have high rates of energy expenditure. Therefore, a slight change in organ weight could have a large impact on overall energy expenditure.

The ageing process results in several changes that probably contribute to the loss of muscle mass. First, ageing is associated with a decrease in physical activity, reducing biomechanical forces on skeletal muscle needed for maintenance or growth of muscle mass. Exercise, especially strength training, can reverse the decline in muscle mass in the elderly. Changes in levels of anabolic hormones also contribute to the age-related decline in muscle mass.

Spontaneous and stimulated growth hormone (GH) secretions are decreased with age. Similarly, circulating levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) also decrease with age. Deficiencies in GH and IGF-1 are both associated with reduced protein synthesis and loss of LBM. Decreases in testosterone and estrogen levels probably also play a role in the depletion of LBM. Insulin-mediated suppression of body protein breakdown, unlike other actions of insulin, does not appear to decrease with age. Overall, a decrease in physical activity and decreased levels of anabolic hormones appear to be the likely causes of loss of LBM with ageing.

Changes in body protein content are accompanied by an increase in percent body fat in elderly individuals. During middle age, a doubling of total body fat can occur, and development of obesity becomes a major problem. After 65–70 years of age, however, there is frequently a decrease in body weight that is the result of decreases in both lean and fat mass. However, the decrease in lean mass typically occurs at a greater rate, resulting in an increase in percent body fat and potentially the development of sarcopenia-related obesity.

Several factors contribute to increases in percent body fat in the elderly.