Ageing

Causes, 2024 Revisit

Ageing is caused by the accumulation of damage to the cells. Some of the causes are unavoidable such as ultraviolet radiation, free radicals, and genetic effects; others involve environmental and behavioral influences. Figure 05a summarizes the major causes of ageing, and the consequences.

One characteristic shared by all species is the accumulation of unrepaired somatic damage. Thus, lifelong accumulation of various types of damage; along with random errors in bio-informational processes are the major causes of ageing. Interventions that

		remove damage might counter some of the adverse effects. But macromolecular damage comes in many forms (Figure 05b), many of which have yet to be identified. It might seem more efficient to eliminate damaging molecules, rather than the damage itself. However, some damaging molecules are crucial for normal cellular function we cannot do without. Some time interventions are two edges sword. For example, tissue regeneration elevates cancer risk by increasing the chance of acquiring DNA mutations or epi-mutations.
Figure 05a Causes of Ageing [large image]	Figure 05b Macromolecular Causes [view large image]	While tumour suppressor mechanisms either eliminate cells that acquired extensive damage (apoptosis) or permanently prevent their proliferation (senescence).

When damage levels are not high enough to elicit an apoptotic or senescence response, a potentially more serious situation ensues that is difficult to counter: the gradual accumulation of random changes in DNA or protein, turning tissues into cellular mosaics. Such stochastic (random) changes can reset gene regulatory loops, and randomly alter gene expression patterns on a cell by cell basis. These changes, in aggregate, might compromise tissue function, without eliciting immediate cellular responses. Stochastic gene regulatory drift would be difficult to correct. Followings are more detailed descriptions for some specific causes.



DNA Damage - Usually DNA damages (such as from uv light) are corrected by repair enzymes. When the repair mechanism breaks down, it causes a progressive process in ageing, in many age-related diseases like cancer and in genetic diseases such as Down's syndrome, cystic fibrosis and Werner's syndrome. People with DNA repair disorders often have broken chromosomes, following exposure to ionizing radiation or chemicals that affect cell division. Figure 05c depicts two processes to repair DNA damage inflicted by UV light, which causes an extra covalent bond to form between adjacent pyrimidines, particularly thymines. The emzymes called photolyases absorb energy from visible light and use it to detect and bind to pyrimidine dimers, then break the extra bond.

Figure 05c DNA Repair [view large image]



• Free Radicals in Metabolism - Even though if cellular damage by external causes can be avoided, an inherent problem is bound to arise by internal metabolism. The metabolic pathway in mitochondria relies on the transportation of free electrons, which eventually attach to oxygen and are normally neutralized by hydrogen ion to form water. This is usually referred to as respiration. Sometimes the process breaks down; the electrons do not attach to the oxygen and instead, attach to other oxygen species. Specific molecules, each carrying a wayward electron, were created. They are call free radicals such as superoxide (O₂^-) and peroxide (O₂^2-) - collectively called reactive oxygen species or ROS (Figure 06a). These free radicals are highly reactive and can do tremendous damage to the cell. The ROS can indiscriminately damage anything that gets in their way - proteins, fats, RNA, and DNA. The effect is cumulative and a serious problem will occur if ROS numbers get too high. Not surprisingly, the cell has responded to this threat by creating various enzymes that bind to free radicals and inactivate them. Collectively, molecules that destroy free radicals are called anti-oxidants. Figure 06b shows one of the anti-oxidants, superoxide dismutase enzyme (SOD), in action. It is present in nearly all cells exposed to oxygen.
  
  Aging is probably the result of the breakdown in the cellular safety nets - not enough anti-oxidants are produced naturally. In addition, modern life has enormously increased the number of toxic free-radicals introduced into our bodies every day from the

  			surrounding environment. The most significant sources of excess free-radicals are dietary or environmental. Dietary sources are usually fats, either rancid or hydrogenated fats, and fats that have been heated to high temperatures during cooking. Environmental pollutants include automobile exhaust, cigarette smoke and numerous other chemicals, physical exercise, stress, and radiation. Table 04 summarizes the variety of defenses to prevent or repair molecular damage caused by free radicals, but as a group they are thought to be imperfect. Some evidence indicates that certain of the defenses also become less effective over time (ageing). New study found that in the course of ageing, certain people are more vulnerable than others to age-related damage from ROS, and genes related to memory and learning appear to be more vulnerable than other genes. Further research is needed to identify the causes.
  Figure 06a ROS [view large image]	Figure 06b SOD [view large image]	Table 04 Defenses [view large image]

  Lately in 2008, it is suggested that drinking or eating isotopes can slow down the chemical reactions with ROS. It is because the heavy isotopes form stronger covalent bonds than their lighter counterparts. While the effect applies to all heavy isotopes, including those with the elements of life such as carbon-13, nitrogen-15 and oxygen-18, it is most marked with deuterium (heavy water with one extra neutron) as it is proportionally so much heavier than hydrogen. Deuterated bonds can be up to 80 times stronger than those containing hydrogen (Figure 06). The idea has been tested on fruit flies. It is found that large dosages were deadly, smaller quantities increased lifespans by up to 30%, and herein lies some problems with this big idea:

  Figure 06c ROS Damage Control [view large image]

  • Safety - Although carbon-13 and the other elements of life seem to be essentially non-toxic, the tolerant limit for deuterium in mammals is at about the 20% mark, and at 35% it becomes lethal.
  • Cost - The current market price for deuterium is about US$300 per liter - much more expensive than gasoline. Method is available to extract deuterium from water, but there is no incentive to produce them in bulk.
  • Delivery - Another problem is to deliver the isotopes to the specific sites. Something called "ifood" has been developed to do the job. It adds the isotopes to the essential amino acids not produced by the body, the reinforced amino acids will thus incorporate into the proteins. Another possibility is to feed deuterated water or isotope-enriched amino acids to farm animals.
  • Ageing Causes - It is now understood that ageing has multiple underlying causes. Free radical damage alone cannot account for all the biological changes that happen with old age. It is doubtful that drinking deuterium laced water alone would stop ageing altogether.
  
  An article in "New Scientist, May 16-22, 2015" reports that "Heavy Fat" metabolized in yeasts make them 150 times as resistant to ROS as those given regular fatty acid. The "Heavy Fat" chemical structure is identical to the regular one except that the hydrogen atoms are replaced by deuterium. A trial with the similar substance on patients with Friedreich's ataxia (this disease is caused by free radical damage to the nerves responsible for movement) will be launched in June, 2015.
  
  
• AGEs (Advanced Glycation End products) - Another prominent causes of somatic damage is related to "reducing sugars", which react with carbohydrates and free amino groups, resulting in difficult-to-degrade AGEs. They accumulate in long-lived structural proteins, such as collagen and elastin increasing the stiffness of blood vessels, joints and the bladder, and impairing function in the kidney, heart, retina and other organs.



Telomere - The telomeres lie at the tips of the chromosome. They have hundreds to thousands of repeats of a specific 6-nucleotide DNA sequence. The telomeres lose 50 to 200 of these nucleotides at each mitosis; gradually shortening the chromosome. After about 50 divisions, a critical amount of telomere DNA is lost, which somehow signals the cell to stop mitosis. The cell may remain alive for a while but is unable to divide further. Some have likened the process of telomere shortening to a genetic biological clock that winds down over time. Today, researchers continue to probe the telomeric "timepiece," hoping to better understand the aging process. For example, It is found that in yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senes-cence in higher eukaryotic cells. It is also found that the amount and length of telomeric DNA in human fibroblasts§ does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. But it is not yet clear whether this loss of DNA has a causal role in senescence. Research in 2007 found the critical telomere length to be 12.8 repeats long - any shorter and the chromosomes began to fuse together at their ends. Another study in 2008 found people who exercised vigorously 3 hours/week had longer telomeres and were biologically 9

Figure 07a Telomere etc. [view large image]

years younger than people who did under 15 minutes. It has been known for some time that the telomerase enzyme, which is present naturally in some mammalian cells, can prevent the telomeres from unraveling.

One of the 2008 studies confirms that at least one type of human cell can indeed be restored to a youthful state by boosting telomerase levels. The other suggests that boosting telomerase can result in longer life in mice. The concerns are on its side effect in promoting the growth of cancer cells as well. It is proposed that the treatment to extend human lifespan could be combined with cancer drugs to offset any enhanced cancer risk. In short, we want the best of both worlds - allowing cell division to happen when we need it (in normal cells) but not to happen when we don't (e.g., in cancer cells).



Inflammation - As a consequence of the shortening of the telomere, the worn-out cells either commit suicide or sitting there without further dividing. The problem with these inactive cells is more than un-dividing, they secrete inflammatory chemicals that damage other healthy cells leading to the trail of senescence, which has been linked to muscle wasting, cataracts, glaucoma, Alzheimmer's, Parkinson's, osteoporosis, arthritis, heart failure, high blood pressure, cancers, and lung, liver, kidney, skin disorders.

Figure 07b Ageing Caused by Worn-out Cells [view large image]

There are many methods proposed to deal with the problem including :



• Senescent Cell Elimination - Destroying senescent cells by drug has been tested on mice. Two drugs for inducing cancer cells to commit suicide are identified as effective in killing senescent cells. It significantly delayed the onset of age-related conditions such as hunchback and cataracts. They are also stronger, looked younger. But it may not be a good idea to kill all the senescent cells because some of them do perform useful functions such as stopping tumour formation, wound healing, and embryo development.


• Stopping the Secretion of Harmful Chemicals - It is found that an existing drug called Rapamycin can do the job expanding the lifespan of mice by about 10%. However, this drug also weakens the immune system and been linked to increasing risk of diabetes. There are on-going researches to find the Rapamycin-like substance without such side effects.


• Limiting the Impact of Inflammation - There are many ways to alleviate the effect of inflammation including painkillers, food restriction, regular exercise, ... mostly involving the change of lifestyle (to healthier habits).

There are social implications on extending lifespan. Some researchers on ageing suggest that the effort is on staving off age-related diseases, relieving the suffering. Eventually, we will die from the depletion of stem cells as demonstrated by the blood sample of an 115 years old Dutch woman, who had only 2 left at the end while a healthy person would have about 1500 such cells. See original article on "Secret to Old Age Health" in New Scientist, 16 September 2015.


• Program Death - Recent research in 2003 points to another biological clock, which determines the life span of an organism. It is found that although the yeast cell normally goes through about 30 cell divisions in its five-day life span, DNA errors in daughter cells started appearing 100 times faster than normal after about 25 cell divisions - the equivalent of middle age in humans. It is noticed that about 80 percent of cancers are diagnosed in people over 55. Since both yeasts and humans use similar mechanism for copying DNA, so the rapid accrual of mutations after midlife is probably not coincidental. It could have something to do with an accumulation of damaged proteins within the cell or with breakdown in the proteins that control DNA replication and repair or with damage in the DNA itself - there is no definite answer at this point. But there seems to be a powerful force in all cells that operates on its own clock with a predetermined expiration date. (The idea that ageing is programmed was missed by evolutionary geronotologists, who recognized that natural selection could not, and would not, bring about such a fate except in very special circumstances).



• The Genes of Ageing - Another recent research on ageing has identified a gene in the roundworm called daf-2. When this one gene is mutated (its function destroyed), the life span of the organism is doubled. This daf-2 gene can be considered a "master gene" of aging. This is because its protein can control the activities of many other genes. Its expression gradually shuts down the cellular repair mechanism as we aged. Cellular damages are inevitable; all multicelluar organisms eventually succumb to the exposure of chemicals, pathogen, extreme temperature and UV radiation because of the crumbling repair mechanism.



• Longevity Genes - Longevity is known to be primarily a matter of environment such as diet, smoking, ... Genetics are thought to contribute to only about 25-30% of the variation in survival to 85 years of age - roughly the average lifespan in developed countries. However, research in 2010 reveals that a cluster of 150 variants in DNA sequence can be used to predict (with 77% accuracy) whether a person has the genetic wherewithal to live to 100 year old. The key factor seems to be the ability to overcome the adverse effects rather than the absence of bad genes. Much more studies are needed to confirm this finding.



• Mitochondrial Theory of Ageing - Mitochondria are little pockets of energy within cells, shouldering the important task of converting food into usable energy forms. To meet demands, every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes, which encode a few mitochondrial proteins. This theory proposes that accumulation of mutations in mitochondrial DNA leads to progressive bioenergy deficiency, cellular damage, degeneration and eventually death. To test the theory, mice were genetically engineered to have mtDNA polymerase with poor proof-reading activity, and hence an enhanced mutation rate.

These mice develop signs of premature ageing and die aged about a year instead of 2-3 years. The finding strongly support the idea that mutations in mitochondrial DNA can cause at least some features resembling ageing instead of just correlative (the manifestations of growing old). Figure 08a compares the mutating mice (mut) with the littermate wild-type (wt) at the age of ~ 40-45 weeks. It shows the mtDNA-mutator mice with reduced body size, kyphosis (curving of the spine), reduced hair density and different stages of alopecia (baldness) - delineated by dashed line (from bottom to top). New study on human have linked unhealthy mitochondria to Alzheimer's, Parkinson's, type 2 diabetes and other degenerative diseases.

Figure 08a Mutating Mice [view large image]


An unified theory of ageing is proposed in 2011 linking telomere damage in the cell nucleus to mitochondrial dysfunction.

It is found that activation of the p53 protein in response to telemere damage can have different effects. In proliferative cells, p53 halts both cell growth and DNA replication, potentially causing apoptotic cell death (it also kills mutant cells). The 2011 new report indicates that p53 also represses the expression of PGC-1 genes in mitochondria, reducing the function and number of these organelles, and so leading to age-related dysfunction of mitochondrion-rich, quiescent tissues. This derangement also leads to the generation of toxic intermediates such as reactive oxygen species (ROS), which produce further

Figure 08b Unified Theory of Ageing [view large image]

damage in mitochondrial DNA setting up a vicious cycle of mitochondrial dysfunction (Figure 08b). Thus many of the causes for ageing are related through the action of p53. Paradoxically, this cancer eliminating protein also carries the penalty of ageing.




It is reported in 2006 that a new method enables the determination of aging in different parts of the human body. It is found that the body's front-line cells endure the roughest life, last the briefest time and are constantly replaced - these include the epithelial cells lining the gut (five days), the epidermal cells covering the skin's surface (2 weeks). The left diagram of Figure 08c shows the average age of other types of cell (yellow circles); those indicate by red circles are still under investigation. Now if the skin is so young, why don't we retain a smooth complexion even into old age? The answer lies with the mtDNA, which accumulates mutations at a faster rate than DNA in the nucleus. In skin, for instance, mitochondrial mutations are thought to be responsible for the gradual loss in the quality of collagen, the skin's scaffolding, which is why skin loses its shape and forms wrinkles. If we ever find ways to protect or repair mtDNA, this new discovery means that

Figure 08c Aging of Organs [view large image]

we could significantly delay ageing. The diagram on the right of Figure 08c is a 2013 update on the aging of organs.




		Autophagy - The process of autophagy begins when a membrane within the cell engulfs cell components that are to be broken down; this creates the autophagosome, which then fuses with a lysosome. The contents within are degraded by various enzymes (see Figure 08d). As shown in Figure 08e, malfunction of the process causes many kind of diseases including ageing.
Figure 08d Autophagy, Process [view large image]	Figure 08e Autophagy, Malfunction

Evidences strongly suggest that ageing is associated with a decline in autophagy. The failure of the process to degrade proteins would increase the risk of metabolic diseases. It causes a steady accumulation of sugar and fat in the body which in turn, further suppresses autophagy. The vicious circle would lead to all kinds of ageing-related disorders. The benefit of caloric restriction to slow down ageing is one example that provides a tentative link to autophagy (in animals). Research has also shown that exercise can stimulate autophagy; it is speculated that sedentary lifestyles may suppress our capacity to maintain the high level of autophagy that helped to keep our ancestors healthy. An autophagy-stimulating drug called rilmenidine is being tested in an ongoing clinical trial for safety in patients with Huntington's disease. It is hoped that the trials can move to include other neuro-degenerative disease - an area where many clinical researfdhers see the greatest promise in autophagy-targeting therapeutics.

	The unique characteristics of axolotls and other amphibians are part of the evolutionary experimentation that occurred as life transitioned from water to land (see the external grills in Figure 08f). Axolotls offer a fascinating glimpse into this evolutionary process because they retain characteristics of both aquatic and terrestrial life, reflecting an intermediate stage.
Figure 08f Axolotls and Their Habitat [view large image]	Land-dwelling animals evolved to suit life on land better, leaving behind the characteristics that once bridged the gap between water and land.

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