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  • Ageing

    Ageing


    • Ageing, also spelled aging, is the process of becoming older. The term refers especially to human beings, many animals, and fungi, whereas for example bacteria, perennial plants and some simple animals are potentially immortal. In the broader sense, ageing can refer to single cells within an organism which have ceased dividing (cellular senescence) or to the population of a species (population ageing).

      In humans, ageing represents the accumulation of changes in a human being over time, encompassing physical, psychological, and social change. Reaction time, for example, may slow with age, while knowledge of world events and wisdom may expand. Ageing is among the greatest known risk factors for most human diseases: of the roughly 150,000 people who die each day across the globe, about two thirds die from age-related causes.

      The causes of ageing are uncertain; current theories are assigned to the damage concept, whereby the accumulation of damage (such as DNA oxidation) may cause biological systems to fail, or to the programmed ageing concept, whereby internal processes (such as DNA methylation) may cause ageing. Programmed ageing should not be confused with programmed cell death (apoptosis).

      The discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats has motivated research into delaying and preventing ageing.

      Human beings and members of other species, especially animals, necessarily experience ageing and mortality. Fungi, too, can age. In contrast, many species can be considered immortal: for example, bacteria fission to produce daughter cells, strawberry plants grow runners to produce clones of themselves, and animals in the genus Hydra have a regenerative ability with which they avoid dying of old age.

      Early life forms on Earth, starting at least 3.7 billion years ago, were single-celled organisms. Such single-celled organisms (prokaryotes, protozoans, algae) multiply by fissioning into daughter cells, thus do not age and are innately immortal.



      • Some evidence is provided by oxygen-deprived bacterial cultures.
      • The theory would explain why the autosomal dominant disease, Huntington's disease, can persist even though it is inexorably lethal. Also, it has been suggested that some of the genetic variants that increase fertility in the young increase cancer risk in the old. Such variants occur in genes p53 and BRCA1.
      • The reproductive-cell cycle theory argues that ageing is regulated specifically by reproductive hormones that act in an antagonistic pleiotropic manner via cell cycle signalling, promoting growth and development early in life to achieve reproduction, but becoming dysregulated later in life, driving senescence (dyosis) in a futile attempt to maintain reproductive ability. The endocrine dyscrasia that follows the loss of follicles with menopause, and the loss of Leydig and Sertoli cells during andropause, drive aberrant cell cycle signalling that leads to cell death and dysfunction, tissue dysfunction (disease) and ultimately death. Moreover, the hormones that regulate reproduction also regulate cellular metabolism, explaining the increases in fat deposition during pregnancy through to the deposition of centralised adiposity with the dysregulation of the HPG axis following menopause and during andropause (Atwood and Bowen, 2006). This theory, which introduced a new definition of ageing, has facilitated the conceptualisation of why and how ageing occurs at the evolutionary, physiological and molecular levels.
      • A buildup of waste products in cells presumably interferes with metabolism. For example, a waste product called lipofuscin is formed by a complex reaction in cells that binds fat to proteins. This waste accumulates in the cells as small granules, which increase in size as a person ages.
      • The hallmark of ageing yeast cells appears to be overproduction of certain proteins.
      • Autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Autophagy is enhanced in obese mice by caloric restriction, exercise, and a low fat diet (but in these mice is evidently not related with the activation of AMP-activated protein kinase, see above).
      • Teenagers lose the young child's ability to hear high-frequency sounds above 20 kHz.
      • Some cognitive decline begins in the mid-20s.
      • Wrinkles develop mainly due to photoageing, particularly affecting sun-exposed areas (face).
      • After peaking in the mid-20s, female fertility declines.
      • People over 35 years old are at risk for developing presbyopia, and most people benefit from reading glasses by age 45–50. The cause is lens hardening by decreasing levels of α-crystallin, a process which may be sped up by higher temperatures.
      • Hair turns grey with age.Pattern hair loss by the age of 50 affects about half of males and a quarter of females.
      • Menopause typically occurs between 49 and 52 years of age.
      • In the 60–64 age cohort, the incidence of osteoarthritis rises to 53%. Only 20% however report disabling osteoarthritis at this age.
      • Around a third of people between 65 and 74 have hearing loss and almost half of people older than 75.
      • By age 80, more than half of all Americans either have a cataract or have had cataract surgery.
      • Frailty, defined as loss of muscle mass and mobility, affects 25% of those over 85.
      • Atherosclerosis is classified as an ageing disease. It leads to cardiovascular disease (for example stroke and heart attack) which globally is the most common cause of death.
      • The maximum human lifespan is suggested to be 115 years "for the foreseeable future". The oldest reliably recorded human was Jeanne Calment who attained 122 years and died in 1997.
      • DNA methylation: The strong effect of age on DNA methylation levels has been known since the late 1960s. Horvath hypothesised that DNA methylation age measures the cumulative effect of an epigenetic maintenance system but details are unknown. DNA methylation age of blood predicts all-cause mortality in later life. Furthermore, prematurely aged mice can be rejuvenated and their lives extended by 30% by partially "resetting" the methylation pattern in their cells (a full reset leads to undesirable immortal cancer cells). This resetting into a juvenile state was experimentally achieved by activating the four Yamanaka DNA transcription factors – Sox2, Oct4, Klf4 and c-Myc (which have previously been routinely used for producing young animals from cloned adult skin cells).
      • Telomeres: In humans and other animals, cellular senescence has been attributed to the shortening of telomeres at each cell division; when telomeres become too short, the cells senesce and die or cease multiplying. The length of telomeres is therefore the "molecular clock", predicted by Hayflick. However, telomere length in wild mouse strains is unrelated to lifespan, and mice lacking the telomerase enzyme do not have a dramatically reduced lifespan. Laboratory mice's telomeres are many times longer than human ones. Another caveat is that a study following nearly 1000 humans for ten years showed that while some humans do shorten their telomeres over time, a third of the participants did not.
      • A variation in the gene FOXO3A has a positive effect on the life expectancy of humans, and is found much more often in people living to 100 and beyond – moreover, this appears to be true worldwide. FOXO3A acts on the sirtuin family of genes which also have a significant effect on lifespan in yeast and in nematodes. Sirtuin in turn inhibits mTOR.
      • Caloric restriction leads to longer lifespans in various species, an effect that is unclear, but probably mediated by the nutrient-sensing function of the mTOR pathway.
      • mTOR, a protein that inhibits autophagy, has been linked to ageing through the insulin signalling pathway. mTOR functions through nutrient and growth cues leading scientists to believe that dietary restriction and mTOR are related in terms of longevity. When organisms restrict their diet, mTOR activity is reduced, which allows an increased level of autophagy. This recycles old or damaged cell parts, which increases longevity and decreases the chances of being obese. This is thought to prevent spikes of glucose concentration in the blood, leading to reduced insulin signalling. This has been linked to less mTOR activation as well. Therefore, longevity has been connected to caloric restriction and insulin sensitivity inhibiting mTOR, which in turns allows autophagy to occur more frequently. It may be that mTOR inhibition and autophagy reduce the effects of reactive oxygen species on the body, which damage DNA and other organic material, so longevity would be increased.
      • A decreased Growth hormone/Insulin-like Growth Factor 1 signalling pathway has been associated with increased life span in various organisms including fruit flies, nematodes and mice. The precise mechanism by which decreased GH/IGF-1 signalling increases longevity is unknown, but various mouse strains with decreased GH and/or IGF-1 induced signalling share a similar phenotype which includes increased insulin sensitivity, enhanced stress resistance and protection from carcinogenesis. The studied mouse strains with decreased GH signalling showed between 20% and 68% increased longevity, and mouse strains with decreased IGF-1 induced signalling revealed a 19 to 33% increase in life span when compared to control mice.
      • Over-expression of the Ras2 gene increases lifespan in yeast by 30%. A yeast mutant lacking the genes sch9 and ras2 has recently been shown to have a tenfold increase in lifespan under conditions of calorie restriction and is the largest increase achieved in any organism.
      • Evolutionary theories of ageing: Many have argued that life span, like other phenotypes, is selected. Traits that benefit early survival and reproduction will be selected for even if they contribute to an earlier death. Such a genetic effect is called the antagonistic pleiotropy effect when referring to a gene (pleiotropy signifying the gene has a double function – enabling reproduction at a young age but costing the organism life expectancy in old age) and is called the disposable soma effect when referring to an entire genetic programme (the organism diverting limited resources from maintenance to reproduction). The biological mechanisms which regulate lifespan evolved several hundred million years ago.
      • Some evidence is provided by oxygen-deprived bacterial cultures.
      • The theory would explain why the autosomal dominant disease, Huntington's disease, can persist even though it is inexorably lethal. Also, it has been suggested that some of the genetic variants that increase fertility in the young increase cancer risk in the old. Such variants occur in genes p53 and BRCA1.
      • The reproductive-cell cycle theory argues that ageing is regulated specifically by reproductive hormones that act in an antagonistic pleiotropic manner via cell cycle signalling, promoting growth and development early in life to achieve reproduction, but becoming dysregulated later in life, driving senescence (dyosis) in a futile attempt to maintain reproductive ability. The endocrine dyscrasia that follows the loss of follicles with menopause, and the loss of Leydig and Sertoli cells during andropause, drive aberrant cell cycle signalling that leads to cell death and dysfunction, tissue dysfunction (disease) and ultimately death. Moreover, the hormones that regulate reproduction also regulate cellular metabolism, explaining the increases in fat deposition during pregnancy through to the deposition of centralised adiposity with the dysregulation of the HPG axis following menopause and during andropause (Atwood and Bowen, 2006). This theory, which introduced a new definition of ageing, has facilitated the conceptualisation of why and how ageing occurs at the evolutionary, physiological and molecular levels.
      • Autoimmunity: The idea that ageing results from an increase in autoantibodies that attack the body's tissues. A number of diseases associated with ageing, such as atrophic gastritis and Hashimoto's thyroiditis, are probably autoimmune in this way. However, while inflammation is very much evident in old mammals, even completely immunodeficient mice raised in pathogen-free laboratory conditions still experience senescence.
      • The cellular balance between energy generation and consumption (energy homeostasis) requires tight regulation during ageing. In 2011, it was demonstrated that acetylation levels of AMP-activated protein kinase change with age in yeast and that preventing this change slows yeast ageing.
      • DNA damage theory of ageing: DNA damage is thought to be the common basis of both cancer and ageing, and it has been argued that intrinsic causes of DNA damage are the most important drivers of ageing. Genetic damage (aberrant structural alterations of the DNA), mutations (changes in the DNA sequence), and epimutations (methylation of gene promoter regions or alterations of the DNA scaffolding which regulate gene expression), can cause abnormal gene expression. DNA damage causes the cells to stop dividing or induces apoptosis, often affecting stem cell pools and hence hindering regeneration. However, lifelong studies of mice suggest that most mutations happen during embryonic and childhood development, when cells divide often, as each cell division is a chance for errors in DNA replication.
      • Genetic instability: In heart muscle cells, dogs annually lose approximately 3.3% of the DNA in their heart muscle cells while humans lose approximately 0.6% of their heart muscle DNA each year. These numbers are close to the ratio of the maximum longevities of the two species (120 years vs. 20 years, a 6/1 ratio). The comparative percentage is also similar between the dog and human for yearly DNA loss in the brain and lymphocytes. As stated by lead author, Bernard L. Strehler, "... genetic damage (particularly gene loss) is almost certainly (or probably the) central cause of ageing."
      • Accumulation of waste:
      • A buildup of waste products in cells presumably interferes with metabolism. For example, a waste product called lipofuscin is formed by a complex reaction in cells that binds fat to proteins. This waste accumulates in the cells as small granules, which increase in size as a person ages.
      • The hallmark of ageing yeast cells appears to be overproduction of certain proteins.
      • Autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Autophagy is enhanced in obese mice by caloric restriction, exercise, and a low fat diet (but in these mice is evidently not related with the activation of AMP-activated protein kinase, see above).
      • Wear-and-tear theory: The very general idea that changes associated with ageing are the result of chance damage that accumulates over time.
      • Accumulation of errors: The idea that ageing results from chance events that escape proof reading mechanisms, which gradually damages the genetic code.
      • Cross-linkage: The idea that ageing results from accumulation of cross-linked compounds that interfere with normal cell function.
      • Studies of mtDNA mutator mice have shown that increased levels of somatic mtDNA mutations directly can cause a variety of ageing phenotypes. The authors propose that mtDNA mutations lead to respiratory-chain-deficient cells and thence to apoptosis and cell loss. They cast doubt experimentally however on the common assumption that mitochondrial mutations and dysfunction lead to increased generation of reactive oxygen species (ROS).
      • Free-radical theory: Damage by free radicals, or more generally reactive oxygen species or oxidative stress, create damage that may gives rise to the symptoms we recognise as ageing.Michael Ristow's group has provided evidence that the effect of calorie restriction may be due to increased formation of free radicals within the , causing a secondary induction of increased antioxidant defence capacity.
      • DNA oxidation and caloric restriction: Caloric restriction reduces 8-OH-dG DNA damage in organs of ageing rats and mice. Thus, reduction of oxidative DNA damage is associated with a slower rate of ageing and increased lifespan.
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