Ageing is an important social, economic and medical issue as we are living in an increasingly aged society. If we understand how we age we may develop interventions to modulate the ageing process for the benefit of both individuals and society.
Experimental models used to study ageing
The ageing prccess
The genetics of ageing
Resistance to cellular stress and oxidative damage
The IGF-1 insulin pathway
Ageing is an important social, economic and medical issue in view of the demographic changes occurring in the western world as we are living in an increasingly aged society. Ageing is commonly characterised as a progressive, generalised impairment of function resulting in increasing vulnerability to environmental challenges and an increased risk of developing disease.1
In humans changes associated with ageing begin as early as the third and fourth decade and include a progressive reduction in kidney volume and weight and a fall in cardiac output by approximately 1% per year from the third decade onwards in patients with no overt underlying cardiac disease.2 We therefore need to undertake research in order to understand various aspects of the ageing process at every level – molecular, cellular, physiological, pathological etc. If we understand how we age we may develop interventions to modulate the ageing process for the benefit of both individuals and society.
Ageing may be differentiated into either primary or secondary aging (Figure 1). Primary ageing refers to the decline of the ability of an organism to maintain tissue homeostasis over time without the influence of external factors and this involves changes in biochemistry, genetics and signalling at a cellular level. Secondary ageing refers to age-related disease, such as atherosclerosis, that arises in healthy people over time without the involvement of external factors such as smoking etc. Thus, primary ageing provides the biological landscape that is further sculpted by the effects of secondary ageing.
Thus far, there are no treatments or therapies that have been demonstrated to slow or reverse the primary ageing process in humans. Various biomedical issues known to affect longevity do so by their influence on disease development and thus modulate the secondary ageing process. Despite the fact that are still many unknowns in the field of ageing, recent research in various animal models has highlighted a number of important factors that can affect both the primary and secondary ageing process.
Figure 1 – Primary and secondary ageing
Damage associated with cellular metabolism which adversely affects the maintenance of cellular homeostasis
Age-related disease processes that arises in healthy people over time.
Oxidative Stress resulting from free radicals generated by cellular metabolism. May result in damage to proteins, lipids and DNA.
Cardiovascular Disease e.g. elevated cholesterol and hypertension that leads to subsequent atherosclerosis
Mitochondrial DNA and Chromosomal DNA damage with adverse effects upon cell metabolism and gene expression/function
Cancer – secondary to neoplastic changes in cells
Reduction in telomere length leading to limited cell replication, defective cellular repair and cellular senescence
Tissue Atrophy – results in cell loss and reduced functional and regenerative capacity of various organs e.g. heart, liver, kidney.
Dysfunctional protein handling and accumulation of damaged proteins within the cell
A number of tools are available to study the process of ageing ranging from unicellular organisms such as yeast to animal models utilising mice. Although it initially seems somewhat odd to use yeast in the study of ageing this unicellular organism can be used in the laboratory to study the effect of single gene mutations and changes in intracellular protein transcription upon the lifespan of the organism. Indeed, data derived from experiments with yeast helped to establish the awareness of so-called ‘longevity genes’ and the biochemical pathways that they affect. However, it is obviously difficult to attempt to extrapolate data derived from yeast into larger more complicated multicellular organisms.
The transparent nematode Caenorhabditis elegans (roundworm) has also been used as an model to study ageing. A particularly interesting aspect of the biology of C. elegans is that the larva is able to enter a discrete developmental stage termed a ‘dauer’ in the context of food limitation or overcrowding and this inactive form is comparable to hibernation in many ways. Unlike adult worms that live for a few weeks at most, the dauer may survive for many months. The dauer exhibits reduced metabolic activity and an increased resistance to oxidative stress and are believed to have activated a ‘longevity program’. Animals that exit this growth arrested dauer stage have a lifespan comparable to worms that did not enter the dauer stage.
Various mammals including mice, dogs and primates are often studied in an attempt to examine genetic pathways first discovered using more primitive experimental systems such as yeast or worms so that the work is placed in a multicellular context more comparable to humans. Such research has highlighted the importance of the insulin-like growth factor-1 (IGF-1)/insulin pathways in modulating primary and secondary ageing.
In addition, murine studies have been used for important ‘proof of principle’ studies to demonstrate that pharmaceutical agents can modulate the ageing process. Finally, observational studies in humans have highlighted particular genes and lifestyles that are associated with exceptional longevity in humans. The piecing together of various facets of information from multiple biological models has improved our understanding of both the primary and secondary ageing processes.
Why do we age?
The biological state of an organism reflects it’s capacity to regulate and repair many internal biochemical and biological processes as well as effectively deal with the effects of the external environment. This will depend, at least in part, upon the age of the organism. However, although it is apparent that ageing affects all living organisms, why do we age?
Consideration of ageing from the perspective of evolutionary genetics suggests that longevity genes are not common such that we may suffer from the effects of secondary ageing. Although it has been argued that there would be a selection pressure to pass on any longevity genes to the next generation, Peter Medawar in 1952 hypothesised that the evolutionary benefit of a longer lifespan was negligible; a hypothesis that provides the basis of the mutation accumulation theory.3
Medawar proposed that the numbers of adults of any specific age would decrease exponentially because of inherent ecological mortality even in the absence of any ageing process. Thus, even if an animal possessed a longevity gene which mitigated the effects of ageing, the benefit would only be realised if the animal successfully escaped all causes of death (predators, disease etc.) or was reared in a protected environment.1,3
Therefore, longevity genes have not been subjected to strong selective pressures in the natural world. Despite this, it has become apparent that there is a clear relationship between the genetic make-up of an individual and the ageing process and this will be explored in detail later.
In 1957 George Williams proposed that genes that were of benefit to an organism at a young age could be detrimental at an older age - a concept termed antagonistic pleiotropy. These deleterious ‘late-acting alleles’ would be passed on to each generation as the benefits of the gene would be expressed at a reproductive age.4 Although an intriguing concept, there are very few clear-cut examples of antagonistic pleiotropy.5
Williams suggested a theoretical example of calcium metabolism whereby the efficient absorption of calcium and subsequent calcification of bones would benefit animals during development and growth but could facilitate vascular calcification in later life leading to cardiovascular disease.1 It is pertinent, however, that recent work suggests that the p53 gene exhibits antagonistic pleiotropy.
The expression of p53 is upregulated in cells exhibiting DNA damage (e.g. following UV irradiation) and p53 induces cell cycle arrest and the induction of cell death. As a result, the p53 gene is often referred to as the ‘Guardian of the Genome’ as it provides a defence against the development of cancer. However, the p53 gene is also important in cellular ageing. For example, there is impaired tissue homeostasis and accelerated primary ageing if the anti-proliferative properties of p53 expression are applied to normal stem cells.1,6,7
Furthermore, Tyner and colleagues studied transgenic mice that overexpressed p53 and demonstrated that, although they were significantly resistant to spontaneous tumour formation compared to control mice, the p53 overexpressing mice showed signs of accelerated ageing.7 The features of accelerated ageing included age-related organ atrophy, reduced wound healing capacity and a reduced stress response compared to control mice.7 Furthermore, p53 signalling may play a role in other premature ageing phenotypes via altered protease activity,.8 Although the exact role of p53 in the ageing process of humans is debatable it does illustrate the concept of antagonistic pleiotropy.
The process of ageing involves many physiological changes in an organism. Over time an organism exhibits a reduced ability to maintain cellular homeostasis and this will lead to reduced growth, defective repair and accumulated damage at a cellular and tissue level. Thomas Kirkwood suggests that the ‘disposable soma theory’ is an appropriate way of interpreting these cellular changes that occur over time.1,9 The disposable soma theory considers how organisms allocate key resources such as energy between diverse processes such as growth, reproduction, cellular repair etc. Each organism will achieve a balance of resource allocation according to its particular ecological environment. For example, humans allocate more energy to monitoring DNA integrity and undertaking DNA repair than mice due to different environmental pressures and this is reflected in the higher incidence of tumours in mice.1
This resource allocation can vary depending upon environmental changes such as increased food availability or a colder temperature. Somatic maintenance aims to provide the organism with a sound physiological condition that would be associated with survival to reproductive age and the opportunity to reproduce. Therefore, the slow accumulation of DNA damage will have no significant impact upon the survival of the species as long as energy is allocated to thermogenesis, growth and reproduction.
Mechanisms of ageing
Before we consider the potential for influencing primary ageing in humans, the fundamental mechanisms of primary ageing need to be explored. There are many cellular and molecular alterations that arise during the ageing process. These changes facilitate the age-related damage seen in older patients and form a complicated web as molecular alterations can affect each other. For example, an increase in free radical production could lead to a secondary increase in DNA damage. For ease of consideration the major theories are discussed individually.
Free radical theory and mitochondrial damage
Although oxygen sustains life, it may be a major culprit in the ageing process. Mitochondria utilise oxygen and glucose to form ATP to drive energy dependent processes. However, this process also generates oxygen free radicals that are inherently unstable and reactive and are members of the family of reactive oxygen species (ROS). ROS can react with various constituents of the cell leading to extensive damage to mitochondrial DNA (mtDNA), proteins and lipid membranes. There is an accumulation of mtDNA mutations with age that is likely to be related to cell stress and ROS.10
Mitochondria that exhibit increased levels of mtDNA mutations are likely to have impaired ATP production. Furthermore, there is significant evidence for increased age-related changes in cells such as cytochrome c-oxidase (COX)-deficient cells that develop increased mtDNA damage.1
Antioxidants such as vitamins C and E as well as superoxide dismutase (SOD) act as a cellular defence mechanism to limit ROS-mediated damage. However, the defence mechanism is limited and mtDNA damage does occur over time.10 The enzyme SOD has an important role in dealing with ROS and converts the superoxide anion into hydrogen peroxide that is further reduced to by the enzyme catalase to form oxygen and water.
Mice that lack the mitochondrial form of SOD incur severe pathology associated with excess free radicals11 and it is also of interest that treatment of the nematode C. elegans with synthetic SOD and catalase mimetics increased lifespan by 44%.12,13 However, other researchers have not found any effect of anti-oxidants upon the lifespan of C. elegans14 so there is still debate regarding the role of oxidative stress and anti-oxidants in the ageing process.
Telomere loss and ageing
Telomeres are specialised regions located at the end of the DNA sequence and act to protect the ends of chromosomes. Each telomere is formed from repeated hexanucleotides - (TTAGGG)n - and each cellular replication results in a reduction in the length of the telomere.15 Although the telomere acts to prevent uncontrolled and cancerous cellular division, it is argued that it directly contributes to the aging process as the number of cell divisions that a cell may undergo is capped.
Cells exhibit an age-related decline in their capacity to undergo cell division and this decline may indeed be related to the inexorable reduction in telomere length that accompanies each cell division.15,16. Cancer cells, germ cells and some adult stem cells possess the enzyme telomerase that prevents telomere shortening thereby resulting in a cell with an unlimited potential for cell division.1 From the perspective of human ageing it is important to note that telomere length is not fixed and there is significant variation between individuals.17
It is clear that telomeres play an important role in genetic stability and the lack of telomeres has been related to a number of diseases including thyroid cancer and the progeroid syndromes.1 Telomere length is not only influenced by genetic make-up17and the number of cell divisions but by biological stresses especially oxidative stress.20 This illustrates the potential for interaction between different factors that affect ageing as oxidative stress may result in telomere shortening that affects the capacity for cell replication in addition to causing damage to cell proteins, lipid membranes, mtDNA etc.
Protein turnover and heat shock proteins
The regulation of protein turnover is critically important in the maintenance of cellular functions. Protein turnover removes proteins that are dysfunctional or no longer required but over time this process becomes less efficient. The accumulation of such unwanted and redundant proteins is associated with a number of age-related diseases such as cataracts, Alzheimer’s disease and Parkinson’s disease.1 For example, some patients develop Parkinson’s disease due to genetic mutations affecting protein handling such as the “Parkin” gene on chromosome 6. This gene reduces the rate of damaged protein removal with a consequent increase in ROS and oxidative stress within the cells that lead to cell death and loss of dopaminergic neurones of the substantia nigra.21
Therefore, although the reduced efficiency in intracellular protein turnover that occurs over time would be deemed to be a primary ageing process, the consequent age-related accumulation of damaged proteins appears critical in a number of diseases that are believed to result from secondary ageing. This illustrates the close relationship between primary and secondary ageing. It is also of interest that caloric restriction (see later) enhances protein turnover and this may play a role in the prolongation of lifespan associated with caloric restriction.22
Heat shock proteins (HSP) are specialised proteins that enable a cell to adapt to sudden changes in their external environment such as an increase or decrease in temperature (hence their name). HSPs were first discovered in fruit flies in the 1960s but are ubiquitously expressed. Although expressed at low levels in normal conditions HSPs are rapidly upregulated in response to many biological stresses such as hypoxia or exposure to toxins or UV light. HSPs act as molecular chaperones and facilitate efficient protein transfer throughout the cell Some HSPs have enzymatic activity and can degrade unwanted or potentially toxic cellular constituents. HSP production declines with increasing age in animals and this may partly explain why older patients exhibit an increased morbidity and mortality when exposed to acute physical stress.23
The reduction in HSP production is important at a cellular level since cells will become more vulnerable to injury and cell death. The fall in HSP production becomes more marked as cells reach senescence.23 It is also noteworthy that HSPs are also under scrutiny by oncologists as they may represent a therapeutic target for cancer treatments.24,25
DNA synthesis and repair
During a lifetime DNA will gradually develop damage through a wide variety of mechanisms and this damage will eventually lead to the dysfunction of genes, proteins and cells. The complicated systems for monitoring DNA integrity and maintaining and repairing DNA involves many enzymes, is energy dependent and may also be unable to fully correct the DNA damage.
Currently, helicase enzymes are thought to play a significant role in ageing. Helicases act to unwind the double helix structure of DNA to enable gene transcription and replication to occur. Most progeroid syndromes are related to failures in genomic maintenance. For example, a null mutation at the WRN locus, which codes for the RecQ family of DNA helicases, is associated with the autosomal recessive human progeroid syndrome, Werner syndrome (WS) or progeria adultorum.26,27
The cells of WS patients are characterised by genome instability, rapid cell senescence and increased cancer risk.1 The clinical manifestations are often dramatic secondary age-related changes within many organs although curiously mental development and function is usually normal.27 WS patients have a reduced life expectancy due to the increased risk of neoplasia and age-related organ changes and atrophy and this suggests that an accumulation of DNA defects does actively promote the ageing process. Although WS patients are studied to examine the ageing process, it must be stressed that there are differences between accelerated ageing and the phenotype of WS. For example, whilst cardiovascular disease affects both groups, WS patients do not generally develop Alzheimer’s disease or dementia.27
Hutchison-Gilford progeria (HGP) is another disease within the progeroid spectrum and is also characterised by abnormal DNA maintenance. HGP is rare and affected individuals exhibit rapid aging that often commences within the first few months of life.28 HGP is characterised by a failure to thrive followed by accelerated age-related degenerative changes that affect the cutaneous, respiratory, renal, locomotor and cardiovascular systems.
HGP is caused by a mutation of the LMNA gene that codes for lamin A. Lamin proteins have a structural function within the nucleus and facilitate the regulation of gene transcription in the cell nucleus. Patients with HPG have a median survival of around 15 years due to the accelerated atherosclerosis of cerebral and coronary arteries.29 In addition, mutations in the LMNA gene are associated with several other progeroid conditions30 and it is clear that problems with genomic maintenance adversely affect the ageing process.
The curious case of dementia
Although progeroid syndromes such as WS or HGP offer great insights into the genetics and pathobiology of premature ageing, they do not reflect true ageing as mental impairment is not present.31 This is in contrast to significant numbers of senior citizens who possess good age-adjusted physical health but develop dementia. Why do patients with progeroid syndromes exhibit profound age-related changes in many organs but are not obviously predisposed to develop dementia and cognitive impairment?
The intracellular handling of proteins within neurones may be important as it appears that patients with progeroid syndromes exhibit normal protein handling in neurones within the brain. This is not the case in patients who develop Alzheimer’s disease or dementia with Lewy bodies (DLB) in whom protein handling is clearly abnormal. Alzheimer’s disease is characterised by the deposition of β-amyloid (Aβ) in neuritic plaques that promote cellular damage and cognitive dysfunction. In addition, neuronal inclusions of abnormally phosphorylated tau (β2-transferrin) protein form neurofibrillary tangles. DLB arises when Lewy bodies (spherical aggregates of protein) are deposited within the brain, commonly in the substantia nigra, resulting in brain damage. Thus, comparison of patients with progeroid syndromes to elderly patients with dementia highlights the dissociation between pathogenic processes that affects different systems such as the cardiovascular system and the central nervous system. Furthermore, the defect evident in progeroid patients does not appear to be involved in the development of some common forms of dementia.
In the same way that premature ageing in the progeroid syndromes has a genetic cause, it appears that longevity also has a genetic basis. Longevity genes are genes that may act upon either primary or secondary ageing mechanisms to increase lifespan. Theoretically, longevity genes may act by slowing age-related reduction in the ability of a cell to achieve homeostasis by increasing the resistance of the cell to stress or improving the capacity of the cell to undertake genetic repair.
Longevity genes can also affect various biochemical pathways and reduce the risk of age-related disease development. The existence of such longevity genes in humans is supported by the observation that the children of centenarians have a significantly reduced incidence of diabetes mellitus and heart disease compared to age matches controls thereby suggesting inherited genetic protection.30 Rather than affecting one condition, such as Alzheimer’s disease, it is possible that such longevity genes affect a multitude of age-related conditions.
It is clear that human longevity is at least partly inheritable. Family and twin studies suggest that ~25% of the variation in human lifespan is dependent upon genetic profile with the remaining ~75% being related to external environmental influences.30 Furthermore, association studies indicate that longevity does run in families and a recent genome-wide association study has highlighted the genetic signatures associated with exceptional longevity.30,32
The majority of research suggests that the genetic markers found in people living into their early 90s and above primarily affect the secondary aeging process. For example, an Italian report suggested that this patient cohort have a well-preserved and balanced p53-mediated response that reduces their incidence of cancer without accelerating ageing.33 In addition, a large Japanese study of the Okinawa population showed that genetic polymorphisms in HLA affects secondary ageing by reducing the risk of autoimmune and inflammatory conditions.34
Recent work indicated that genetic signatures could be used to predict how long people could live with up to 77% accuracy and also demonstrated that siblings of centenarians have a 4-fold greater chance of reaching their early 90s than age-matches controls.32 There is thus a strong genetic basis for the longevity of individuals who live to 90+ years.30,34
The genetics of ageing has become a fascinating and fast moving field. Substantial research on short-lived organisms has highlighted that the ageing process is subject to regulation by classic cellular signalling and transcription factors.35 Genetic mutations that are associated with increased longevity affect stress response genes or nutrient sensors35 and these mutations have variable expression depending upon whether the organism is exposed to environmental stresses. This research is of great importance as several metabolic pathways that affect ageing and longevity in one species can be identical in another species.30 Therefore, there is real potential that some of the research data on increasing animal longevity could be used to benefit humans.
Telomere length is highly heritable and as such these genetic differences may be important determinants of ageing.17 Telomere length is an important determinant of disease and individuals with shortened telomeres are more likely to develop age-related conditions such as atherosclerosis, vascular dementia and infections.30 If the genetic basis for telomere length can be accurately determined then it may become possible to manipulate telomere length to reduce the risk of developing a host of age-related diseases. However, as yet the specific genes that govern telomere length and function have not yet been clearly identified.30
A relationship between the resistance of an organism to stress and longevity has long been observed. Research has shown that cellular resistance to oxidative and non-oxidative stresses has a positive correlation with mammalian longevity.36 In addition, HSP levels decrease in older animals reducing the ability of an animal to cope with acute stress. These observations highlight the stress response as an important area to examine and attempt to modulate. The study of fruit flies has been of interest as single gene mutations can increase the resistance of the fly to many forms of stress.
One such gene codes for the protein Methuselah (Mth) that is a G protein–coupled receptor involved in ageing. Heterozygote flies have a lifespan that is increased by around 35% and is associated with an increased resistance to starvation, free-radical damage and thermal stress.37 The IGF-1/insulin pathway has also been explored and has been linked with increases in longevity and this will be discussed later.
Anti-oxidants have been associated with longevity and would be predicted to increase the resistance of an organism to oxidative stress. The increase in C. elegans longevity induced by treatment with synthetic SOD and catalase mimetics was previously discussed.11 The role of anti-oxidants in the human ageing process has also been examined. Association studies have shown that healthy centenarians can have altered profiles of anti-oxidants with raised levels of vitamin A and E.38 Furthermore, there are potential clinical applications for anti-oxidants as some limited clinical trials have shown that anti-oxidants, including vitamin E, vitamin C or glutathione, improved insulin sensitivity in diabetic patients.38
This will inevitably help reduce the accelerated secondary age-related changes seen in diabetic patients. However, the exact role that anti-oxidants play in longevity is still questionable. Further research is required to fully characterise the genes and proteins that are key regulators of the resistance to cell stress in humans so that these pathways may be therapeutically exploited for patient benefit.
Many of the genetic and biochemical pathways associated with the ageing process in C. elegans have been determined and the roundworm provides a good model for examining potential longevity genes. As highlighted previously, the larva of C. elegans can activate a longevity program and form the metabolically inactive and stress resistant dauer in times of severe food shortage or overcrowding. The concept of linking lifespan to metabolic rate and activity is described as the ‘rate of living theory’.
The initiation and maintenance of the dauer stage is controlled by several longevity genes such as daf-2, daf-16 and age. Daf-2 encodes a hormone receptor similar to mammalian insulin and IGF-1 receptors and daf-16 encodes for a fork-head transcription factor.36 Mutations leading to the inhibition of daf-2 and daf-16 transcription have been shown to more than double the lifespan of C. elegans.35 In addition, mutations in daf-2 also increase resistance to environmental stresses such as heat and heavy metal toxins.39 It is proposed that this is due to the coordinated over-expression of stress-response genes39 such as catalases, glutathione S-transferases, HSPs and lipases.35
It is important to note that the alterations in IGF-1/insulin pathways in C. elegans can also be extrapolated to other animals. The ageing process has been delayed in Drosophila melanogaster flies when insulin-like signalling has been reduced.40 There is also a 50% increase in fly lifespan if insulin-like receptor or its receptor substrate (chico) is mutated.40 In addition, it has been observed that small dogs that have a mutation that decreases IGF-1 levels live longer than large dogs. From a human perspective, FOXO gene variants and alteration of the IGF-1/insulin pathway is associated with life span in both male and female humans.41
There is evidence of mutations in the IGF-1/insulin pathway within cohorts of humans known to have a higher chance of exceptional longevity such as Hawaiians of Japanese descent, Italians, Ashkenazi Jews, Californians, New Englanders, Germans and Chinese.35,42 However, at this juncture it is important to recognise that it is only specific mutations in the IGF-1/insulin pathway that facilitates longevity. Critically, animals with mutations in the IGF-1/insulin pathway that promote longevity retain insulin sensitivity with other mutations being shown to lead to insulin resistance that has adverse health implications.35
Calorie restriction (CR) extends life span and retards age-related chronic diseases in a variety of species including rats, mice, fish, flies, worms and yeast. It has been shown to be the most effective method of increasing longevity.30,43 In addition, preliminary experimental results from long-term CR studies in primates have also yielded promising initial results showing that CR increases lifespan in mammals.44
CR involves a reduction in caloric intake whilst maintaining all the required nutritional substances required for normal function. There are several marked changes that follow the implementation of CR. A subject will undergo an alteration in body composition with a reduction in fat mass at a macroscopic and microscopic level i.e. the mean size of abdominal fat cells also decreases.45 CR has been shown to affect both primary and secondary ageing processes.45 The underlying hypothesis is that a decrease in metabolic rate and energy flux will subsequently reduce body-wide oxidative stress in accordance with the rate of living theory.45
There are also significant neuroendocrine changes that occur in CR organisms. Research has shown that CR mice exhibit reduced leptin levels, increased adrenal activity and decreased gonadal and thyroid activity and it has been suggested these hormonal changes may facilitate a reduction in the risk of developing some age-related disease such as atherosclerosis.43
In addition, there are some alterations in genetic expression in CR animals. Activation of the sirtuin pathway may protect cells and increase longevity.46 Sirtuins are deacetylases which silence gene expression and CR changes the expression of sirtuins and lead to an increase in insulin sensitivity and increased DNA repair.30,35 Cynthia Kenyon has suggested that sirtuin-mediated inhibition of toxic extra-chromosomal ribosomal DNA circles may underlie their longevity effect.35 In yeast, increased activation of sir-2 can increase longevity by 50% whilst its inhibition reduces life span.43 Resveratol is a polyphenol compound present in red wine that mimics the action of CR and has also been shown to increase longevity in yeast and reduce age-related damage to cells.46
Furthermore, food supplementation with resveratol prolongs lifespan and prevents age-related traits in other short-lived vertebrates.46 Resveratol supplementation in mammals has as yet not reproduced these results.
The TOR kinase pathway has also been associated with longevity. TOR kinase is a nutrient and amino acid sensor that is activated during periods of growth and stimulates cell salvage and survival pathways when inhibited. Inhibition of the TOR kinase pathway stimulates autophagy - a process that involves the autodegradation of cell constituents and is essential for life extension in a variety of organisms.30,35 CR inhibits TOR kinase pathways at a cellular level, increases resistance to cellular stress and shifts energy towards cellular maintenance. TOR kinase inhibition has been associated with increased lifespan in yeast, mice and worms.35 There are important therapeutic implications for this pathway as drugs that inhibit the TOR kinase pathway could theoretically be used to increase lifespan.
Rapamycin is a TOR kinase inhibitor and is also a potent immunosuppressant drug used to prevent transplant rejection. Administration of rapamycin to mice increased lifespan by 14% for females and 9% for males48 and this is an intriguing ‘proof of concept’ result. However, rapamycin is obviously not a suitable agent in view of the associated immunosuppression. Future research is likely to focus upon developing a pharmaceutical intervention to inhibit the TOR kinase pathway without affecting immune cells.
Ageing has been regarded as inevitable. Organisms undergo ageing as there has been little evolutionary pressure to select organisms possessing longevity genes and animals have typically allocated resources to ensure reproductive efficiency. However, medical research into the ageing process has yielded important information about the underlying mechansims involved in the cellular changes in primary ageing as well as the pathogenesis of many age-related diseases. Although there has been comprehensive development of drugs and therapies that can reduce the incidence and development of age-related disease, there are no agents that comprehensively reduce the cellular damage that arises as result of cell metabolism.
Ageing research has become a major field due to the significant demographic changes arising throughout the Western World. For example, dementia is an area of major importance for geriatric medicine. There are currently approximately 750,000 people in the UK with dementia and this will increase to over one million people by 2025.49 The cost of providing care to patients with Alzheimer’s disease in the USA reached $144 billion in 2009 with 5.3 million people being affected.50 The condition has major medical, social, economic and political ramifications for the future.
Primary ageing has been examined in a range of experimental models. The key processes involved have been established and it has been shown that there are genetic factors involved in these processes. Single gene mutations and polymorphisms in yeast, worms and flies have been associated with increased lifespan by increasing resistance to oxidative stress or increasing telomere length. Alterations in the primary mechanisms can also reduce longevity as seen with the genomic instability and DNA damage in the progeroid syndromes that are associated with a profound acceleration of many aspects of the aging process. This research highlights that alterations in the primary ageing process can be may have a genetic basis. The development of strategies to increase lifespan by direct manipulation of primary ageing is not yet available but an improved understanding of the area and further research efforts may bear fruit in due course.
Secondary ageing has been the subject of much study. Large-scale observational studies and genome wide association studies have highlighted a variety of genes associated with exceptional longevity. Many of these genetic alterations seem to impact upon the secondary ageing process by reducing the incidence of diabetes and cardiovascular disease. Inhibition of the IGF-1/insulin and TOR kinase pathways mediated by CR or genetic polymorphisms have clearly been shown to impact upon longevity in a variety of organisms. CR, regarded as the most reproducible method of improving health and increasing lifespan, has also been shown to be of benefit to humans in short-term studies.51
To date, the research has suggested that the risk of developing age-related disease processes can indeed be affected by genetics and dietary alteration (CR). The challenge for the future is to devise novel therapeutic agents to mimic these changes so that ageing may be safely inhibited in humans thereby improving quality of life.
- Ageing may be differentiated into either primary or secondary ageing.
- Organisms undergo aging as there has been little evolutionary pressure to select organisms possessing longevity genes and animals have typically allocated resources to ensure reproductive efficiency.
- Medical research into the ageing process has yielded important information about the underlying mechansims involved in the cellular changes in primary ageing as well as the pathogenesis of many age-related diseases.
- Kirkwood, T.B., Understanding the odd science of aging. Cell, 2005. 120(4): p. 437-47.
- Boss, G.R. and J.E. Seegmiller, Age-related physiological changes and their clinical significance. West J Med, 1981. 135(6): p. 434-40.
- Medawar, P.B., An Unsolved Problem of Biology. 1952, H.K. Lewis & Co: London.
- Williams, G.C., Pleiotropy, Natural Selection, and the Evolution of Senescence. . Evolution 1957. 11: p. 398-411.
- Leroi, A.M., et al., What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? Mech Ageing Dev, 2005. 126(3): p. 421-9.
- Ungewitter, E. and H. Scrable, Antagonistic pleiotropy and p53. Mech Ageing Dev, 2009. 130(1-2): p. 10-7.
- Tyner, S.D., et al., p53 mutant mice that display early ageing-associated phenotypes. Nature, 2002. 415(6867): p. 45-53.
- Varela, I., et al., Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature, 2005. 437(7058): p. 564-8.
- Kirkwood, T.B. and R. Holliday, The evolution of ageing and longevity. Proc R Soc Lond B Biol Sci, 1979. 205(1161): p. 531-46.
- Wallace, D.C., Mitochondrial diseases in man and mouse. Science. , 1999. 283(5407): p. 1482-8.
- Morten, K.J., B.A. Ackrell, and S. Melov, Mitochondrial reactive oxygen species in mice lacking superoxide dismutase 2: attenuation via antioxidant treatment. J Biol Chem. , 2006. 281(6): p. 3354-9.
- Melov, S., et al., Extension of life-span with superoxide dismutase/catalase mimetics. Science, 2000. 289(5484): p. 1567-9.
- Honda, Y. and S. Honda, Oxidative stress and life span determination in the nematode Caenorhabditis elegans. Ann N Y Acad Sci, 2002. 959: p. 466-74.
- Doonan, R., et al., Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev, 2008. 22(23): p. 3236-41.
- Takubo, K., et al., Changes of telomere length with aging. Geriatr Gerontol Int, 2010. 10 Suppl 1: p. S197-206.
- Kim Sh, S.H., P. Kaminker, and J. Campisi, Telomeres, aging and cancer: in search of a happy ending. Oncogene, 2002. 21(4): p. 503-11.
- Graakjaer, J., et al., Allele-specific relative telomere lengths are inherited. Hum Genet, 2006. 119(3): p. 344-50.
- Capezzone, M., et al., Telomeres and thyroid cancer. Curr Genomics, 2009. 10(8): p. 526-33.
- Aubert, G. and P.M. Lansdorp, Telomeres and aging. Physiol Rev, 2008. 88(2): p. 557-79.
- von Zglinicki, T., Oxidative stress shortens telomeres. Trends Biochem Sci, 2002. 27(7): p. 339-44.
- http://ghr.nlm.nih.gov/condition/parkinson-disease. Genetics Home Reference [cited July 14, 2011].
- http://www.anti-aging-guide.com/34proteinturnover.php. Anti-Aging Guide 2009 [cited July 3, 2011].
- http://www.healthandage.com/html/min/nih/content/booklets/research_new_age/page2.htm. National Institute on Aging Website [cited May 23, 2011].
- Wachtel, M. and B.W. Schafer, Targets for cancer therapy in childhood sarcomas. Cancer Treat Rev, 2010. 36(4): p. 318-27.
- Gao, Z., C. Garcia-Echeverria, and M.R. Jensen, Hsp90 inhibitors: clinical development and future opportunities in oncology therapy. Curr Opin Drug Discov Devel. , 2010. 13(2): p. 193-202.
- Zhao, N., et al., A novel mutation of the WRN gene in a Chinese patient with Werner syndrome. Clin Exp Dermatol, 2008. 33(3): p. 278-81.
- http://www.ncbi.nlm.nih.gov/disease/Werner.html. Genes and Disease – Werner Syndrome [cited July 14, 2011].
- http://ghr.nlm.nih.gov/condition/hutchinson-gilford-progeria-syndrome. Genetics Home Reference - Hutchinson-Gilford progeria syndrome [cited June 4, 2011].
- http://emedicine.medscape.com/article/1117344-overview. Medscape emedicine website [cited May 14, 2011].
- Browner, W.S., et al., The genetics of human longevity. Am J Med, 2004. 117(11): p. 851-60.
- Payão, S.L., et al., Werner helicase polymorphism is not associated with Alzheimer's disease. J Alzheimers Dis., 2004. 6(6): p. 591-4.
- Sebastiani, P., et al., Genetic Signatures of Exceptional Longevity in Humans. Science, 2010.
- Salvioli, S., et al., Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol Immunother. , 2009. 58(12): p. 1909-17.
- http://www.okicent.org/. [cited July 21, 2011].
- Kenyon, C.J., The genetics of ageing. Nature, 2010. 464(7288): p. 504-12.
- Kapahi, P., M.E. Boulton, and T.B. Kirkwood, Positive correlation between mammalian life span and cellular resistance to stress. Free Radic Biol Med, 1999. 26(5-6): p. 495-500.
- McGarrigle, D. and X.Y. Huang, Methuselah antagonist extends life span. Nat Chem Biol, 2007. 3(7): p. 371-2.
- Mecocci, P., et al., Plasma antioxidants and longevity: a study on healthy centenarians. Free Radic Biol Med, 2000. 28(8): p. 1243-8.
- Barsyte, D., D.A. Lovejoy, and G.J. Lithgow, Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. Faseb J, 2001. 15(3): p. 627-34.
- Hwangbo, D.S., et al., Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature, 2004. 429(6991): p. 562-6.
- Pawlikowska, L., et al., Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell, 2009. 8(4): p. 460-72.
- Li, Y., et al., Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet, 2009. 18(24): p. 4897-904.
- Heilbronn, L.K. and E. Ravussin, Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr, 2003. 78(3): p. 361-9.
- Cruzen, C. and R.J. Colman, Effects of caloric restriction on cardiovascular aging in non-human primates and humans. Clin Geriatr Med, 2009. 25(4): p. 733-43, ix-x.
- Redman, L.M., et al., Effect of caloric restriction in non-obese humans on physiological, psychological and behavioral outcomes. Physiol Behav, 2008. 94(5): p. 643-8.
- Howitz, K.T., et al., Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003. 425(6954): p. 191-6.
- Valenzano, D.R., et al., Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol, 2006. 16(3): p. 296-300.
- Harrison, D.E., et al., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 2009. 460(7253): p. 392-5.
- http://www.alzheimers.org.uk/site/scripts/documents_info.php?categoryID=200120&documentID=341. Alzheimer Society UK Website- ‘Statistics’ [cited July 6, 2011]
- http://emedicine.medscape.com/article/1134817-overview. EMedicine Website- Anderson H, ‘Alzheimer Disease‘ [cited July 3, 2011]
- Smith, D.L.J., T.R. Nagy, and D.B. Allison, Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest., 2010. 40(5): p. 440-50.