Cells, tissues and organs all change with age and eventually function begins to deteriorate. Ageing is very complex and poorly understood. There are two major groups of theories:

Wyllie and colleagues have worked on cell death since the 1970s. Whereas an injured cell will swell, burst and release its contents, causing an inflammatory and immune cascade, when a cell dies a normal death, it shrivels up and is consumed by nearby cells so fast it never gets a chance to spill its contents. They named their discovery apoptosis (pronounced apotosis), from the Greek for ‘falling off’, as in leaves from a tree. An array of intracellular and extracellular signals can trigger the cell to enter the process of programmed cell death. Apoptosis occurs from the earliest stages of development (e.g. leading to the separation of fingers), is very active during growth and continues throughout life. Aberrant regulation of apoptosis contributes to cancer, autoimmune disorders, neurodegenerative diseases and systemic viral infection.

It is clear that individual cells can undergo programmed death. There has been debate as to whether multicellular organisms carry programmes to self-destruct (‘a ticking clock’). Ageing as a predetermined, genetically controlled process would be supported by the characteristic lifespans of different organisms. A single gene mutation in the roundworm Caenorhabditis elegans doubles its life expectancy to around 6 weeks. This gene, daf-2, codes for a primitive insulin receptor and regulates an array of other genes which influence longevity. This is part of the mechanism that allows the worm to suspend its development when the environment is harsh. The situation is more complex in man, but the insulin pathway is important in diabetes and cancer which has links with ageing.

Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that extend the lifespan of yeast, worms and flies and may be involved in the mechanism by which calorie restriction increases lifespan in animals. There are seven mammalian sirtuins, SIRT1 to SIRT7, which have complex roles in metabolism, homeostasis and the stress response. Different sirtuins are found in the nucleus, mitochondria and cytosol. Major research effort is being targeted at developing sirtuin activators aiming to treat obesity, diabetes and neurodegeneration and even extend lifespan. Resveratrol (a natural compound found in the skin of red grapes and in wine) was thought to be a SIRT-1 activator but the results may have been an artifact. Nevertheless, there is a huge range of Resveratrol supplements for sale on the internet; anti-ageing is big business (see the website of Sirtris Pharma).

Although no genes have been found that double lifespan in man, a study of the genomes of more than 1,000 centenarians, scouring about 300,000 sequence variations for possible links to longevity, has identified around 150 variations in DNA sequence that can predict (with 77% accuracy) whether a person has the genetic wherewithal to live to 100.

Single genetic disorders causing premature ageing (progeria) do occur. These are ‘segmental ageing’ syndromes as they do not result in all the typical features of ageing, but it seems likely that some of the mechanisms involved will be relevant to normal ageing.

• Hutchinson–Gilford syndrome: very rare, sporadic, autosomal dominant causing death around 13 years from MI or stroke. Usually a silent substitution from glycine GGC (A, C, G and T represent the four nucleotide bases of a DNA strand – adenine, cytosine, guanine, thymine) to glycine GGT in codon 608 of the lamin A (LMNA) gene on 1q, which activates a cryptic splice donor site to produce abnormal lamin A. The nuclear fragility of lamin A-deficient cells increases apoptosis and may exhaust stem cell-driven regeneration.
  
• Werner’s syndrome: rare, autosomal recessive progeria of adulthood caused by mutations in a gene on 8p coding for a member of the RecQ helicase family. Characteristic features include premature greying, skeletal changes and death around 50 years. The Werner protein unwinds, separates and repairs damaged DNA and may be important in maintaining telomeres.

In C. elegans, although genotype determines the mean lifespan of a population, individual longevity has a large stochastic component, with several-fold differences observed even with an isogenic population in a uniform environment.

Wear and tear theories claim that ageing is caused by random accumulated injuries from ultraviolet light, physical damage, toxic by-products of metabolism, etc.

The Ageing Cell

Neurons, renal and myocardial cells do not divide and have to last a lifetime, although the numbers fall. Normal human embryonic fibroblasts have a fixed capacity to divide around 50 times, but those from mature subjects have a reduced capacity for reduplication.

One factor contributing to this may be telomerase inactivation in somatic cells (unlike the germ-line). Telomerase maintains telomeres, regions of repetitive non-coding DNA at the tips of chromosomes that protect them from destruction.

When cells divide, the enzymes that replicate DNA cannot continue all the way to the end of the chromosome so telomeres are gradually used up, becoming shorter every time a cell divides. Eventually they reach a critically short length, the cell cannot divide any more and apoptosis may be triggered. The Nobel Prize for medicine 2009 was awarded for the discovery of how chromosomes are protected by telomeres. Telomerase-deficient mice appear prematurely aged and telomerase reactivation resulted in rejuvenation of some tissues. However, this may carry a cancer risk as telomerase reactivation is a possible explanation for the immortality of malignant cells in culture. A commercial blood test is already available to get your telomere length tested and compared to an age-matched sample to ‘assess your biological age’. This is fascinating, but more work is needed, particularly with regard to the relationship to cancer.

Many other features of cells from aged individuals reflect stochastic events. The biochemistry of the cell is noisy. All cellular processes – transcription, translation, protein folding, every enzymic reaction and all the inbuilt regulatory mechanisms – are subject to random errors. The workings of cells get noisier as they get older, and this might contribute to increasing cellular dysfunction with age. Features of cells from aged individuals include:

• Aneuploidy (variable chromosome numbers).
  
• Accumulation of somatic mutations of DNA in the cell nucleus and mitochondria.
  
• Dysregulation of gene expression.
  
• Misfolded proteins tend to aggregate and ‘gum up the works’, e.g. amyloid. Cells deploy ‘chaperones’ to refold misshapen proteins, but this mechanism may be overwhelmed.
  
• Lipofuscin pigment granules accumulate in cytoplasm in liver, kidney and muscle (from damaged red cells).
  
• Oxidative stress and damage as reactive oxygen species are not mopped up by antioxidants and damage key molecules including DNA.
  
• Less effective cellular pumps (a family of proteins called multidrug resistance proteins) fail to remove toxic products from cells.
  
• Adducts on macromolecules, e.g. glycation may reflect failure of processes for repair and turnover of macromolecules.

Ageing Tissues

• Loss or dormancy of stem cells: ageing could in part be due to the inability of stem cells to replenish the tissues of an organism with functional differentiated cells needed to maintain them.
  
• Cross linkages (e.g. disulphide bonds) in collagen and elastin cause increased stiffness in connective tissue especially in skin, elastic laminae of blood vessels, tendons and lens of eye.
  
• Mitochondrial respiratory-chain function (energy release) is less efficient in skeletal muscle.

• Thymic involution and attenuated T-cell-mediated immunity lead to reactivation of quiescent infections, such as TB and varicella. There seems to be a decline in delayed-type skin-hypersensitivity reactions to injected antigens (anergy) in many frail aged subjects.
  
• Autoantibodies occur more frequently (e.g. antiphospholipid antibodies) and are associated with vascular disease, but their significance in older people is uncertain.
  
• Proliferative disorders of the lymphocyte are very common.
  
• Malnutrition and diabetes compound these problems.

Many of the stochastic cellular events described appear to lead to telomere shortening and many drugs with which we are all familiar lengthen telomeres. Whilst this is too simplistic it is increasingly likely that ageing will eventually be understood in terms of interacting genetic, programmed and random events.

Many physiological parameters decline with age, but the magnitude of the decline is hard to estimate. These figures are almost always based on cross-sectional rather than longitudinal studies, which will include individuals within the elderly cohort who have acquired diseases that may affect function, e.g. renal function will suffer as a result of hypertension or diabetes, or whose sedentary lifestyle in retirement has caused cardiorespiratory fitness to decline through disuse. To be attributable to ageing per se, a phenomenon must be universal, intrinsic and progressive. Watching the London Marathon will reveal many 70 or even 80+ year olds fitter than most people in their 30s and 40s.