Aging

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Ageing

Definition of Ageing

Ageing is one of the oldest biological enigmas and a major biomedical problem of the 21st century. Ageing is an almost ubiquitous though not universal phenomenon in nature. It has been a research puzzle for decades as too why lifespan is limited and evolution has not eliminated the phenomenon. To understand ageing it is important to define it as precisely as our current understanding will allow. However, a consensus on a simple definition of ageing has not been achieved, evidence of the lack of an understanding of the mechanisms underlying the ageing process [Li+Al:2014].

Increase in Probability of Death. Ageing is an increased liability to die, or an increasing loss of vigour, with increasing chronological age, or with the passage of life cycle [Comfort:1960]. Ageing is accompanied by deteriorative changes with time during postmaturational life that underlie an increasing vulnerability to challenges, thereby decreasing the ability of the organism to survive [Masoro:1995]. The ageing process renders individuals more susceptible as they grow older to the various factors, intrinsic or extrinsic, which may cause death [Maynard:1962]. Ageing can be defined as the increase in the probability of death within a period of time. In humans, from 0 to 9 years there is decrease in the probability to die in the following year. After age nine the age-specific mortality rate increases and there is an exponential increase in this rate from around 30 years [Arking:2006]. Ageing therefore seems to be a natural phase in many organism's life cycle.

Natural Deterioration. Ageing is observed natural deterioration of bodily functions, organs, and organ systems increasing the onset of disease and pathology, with a resulting loss of function eventually leading to death.

Functional Decline. By teleological criteria, development can be viewed as consisting of early processes that enhance the functional capacity of a system, whereas ageing consists of later processes that diminish or have no effects on ability to function [Kohn:1978]. Ageing is the progressive decline in several but not all physiological functions, resulting ultimately in the thermodynamic equilibrium, i.e. death. Ageing decreases most aspects (functionalities), although some kinds of cancer are less severe in elderly people as a result of diminishing rates of mitosis. Therefore defining ageing simply as functional decline is not sufficient.

Passing of Time. Ageing is generally used to describe a host of time-related alterations in biological entities from molecules to ecosystems [Finch:1990]. Ageing is a progressive, i.e. a time-dependent phenomenon. Ageing is (for a normally developing organism) just the passing of time. It starts when the survival probability curve has reached its maximum (i.e. lowest age-specific mortality rate) and ends with death. However, ageing is fundamentally an event-dependent phenomenon, rather than a time-dependent process [Arking:2006]. Physiological biomarkers are a much more useful index of ageing than is the simple passage of time [Arking:2006].

Ageing as a Disease. Is ageing a disease? Disease is very much a social construction that takes into account statistical data and available therapy. Regarding statistics, ageing is not a disease because it affects all individuals of a species. Statistically speaking, it is a common feature of most living beings. Regarding available therapy and symptoms, the rate of ageing can be modified but the process is not yet treatable, as all humans eventually die and if they are lucky they die of old age, i.e. the result of ageing.

Developmental Process Usually each human follows the same path of growth, development, maturity and senescence [Arking:2006]. The changes from maturity through senescence constitute the ageing process [Rothstein:1982]. All the parts of the life cycle are continuous with one another in process and mechanism [Arking:2006]. Ageing is a naturally developing biological process which limits the adaptive possibilities of an organism, increases the likelihood of death, reduces the lifespan and promotes age pathologies [Frolkis:1982].

Overall, ageing is a process, that involves changes of the structure of an organism. It is multi-factorial and multi-dimensional at its root, occurs gradually, but is degenerative in its consequences as it leads to loss of functionality and ends with death. Ageing could be defined as every irreversible change of living substances as a function of time [Smith:2002], but are all those processes really irreversible? This seems not to be the case. Most definitions of ageing acknowledge that it is related to changes in the organism leading to a loss in adaptability. This loss in adaptability leads to a higher chance of death. Ageing is a time-independent series of cumulative, progressive, intrinsic, and deleterious function and structural changes that usually begin to manifest themselves at reproductive maturity and eventually culminate in death [Arking:2006].

Measuring Ageing

It is important to measure ageing, the rate of ageing and the process of ageing. Otherwise it would not be possible to know whether an organism ages faster or slower than others. Nor would be possible to know whether an anti-ageing intervention is actually working. In practice two different measurement standards are used dependent on whether ageing is measured in a population or in an individual [Arking:2006].

Ageing in population is measured by using the observed age-specific mortality rates to calculate the number of surviving organisms that will likely die in the next time period. On a demographic level ageing is associated with increased mortality with increasing age as well increased susceptibility to age-related disease. If the death number increases, then the population is composed of ageing individuals, i.e. ageing population. The rate of ageing can be calculated based on how long it takes for the mortality rate to double [Arking:2006].

In individuals, ageing is measured by documenting changes in physiological traits, or biomarkers, known to be important to normal functioning and capable of predicting remaining lifespan. The search for such biomarkers of ageing is an important quest of biogerontology. Biomarkers of ageing are usually surrogates of mortality statistics. None have been shown to be predictive of future survival that are better than the age of the individual. A combination of multiple biomarkers (like derived from genomics or other omics) utilized by mathematical models might have the potential to overcome this, e.g. epigenetic markers are promising candidates for being able to reliably predict future mortality [Christiansen+Al:2016]. In the case the observed changes are altered in the direction of loss of function, then the individual is ageing at some calculable rate of loss of function [Arking:2006].

Plasticity of Ageing

Although ageing is quite widespread across species - it is not a universal phenomenon. Ageing is actually an incredibly plastic process which can be sped up (e.g. by mutation), slowed down (e.g. by dietary restriction), totally stopped (e.g. by genetic knockout), or even reversed (e.g. by overexpression of genes) [Berger:2014] [de_Magalhaes:1997]. The exact mechanism of ageing is an enigma. Understanding why certain species exhibit ageing and others do not (negligible senescence and biological immortal species) would revolutionize medicine.

Although defining what exactly is ageing is difficult, yet it is possible to measure it at least reliable on the population level. From this it is clear that the ageing process is quite plastic, which means it varies from species to species and from individual to individual within a species. In fact, there are quite large intraspecies and even bigger interspecies differences in the lifespan of an organism and the rate of ageing. The rate of ageing varies substantially across different species. This is mainly because of genetic differences. Some species live just about a day (e.g. mayfly), while others live centuries (e.g. sharks, whale). Yet other do not appear to have age-related changes, i.e. exhibit negligible senescence (rockfish, lobster, turtle, etc.), and there are even species which have been declared to be immortal (sea squirts, jellyfish, hydra, flatworms, etc.). The naked-mole rat might be the first mammal that has been declared to exhibit negligible senescence. Although it lives 9 times longer than similar-sized mice and only shows slight age-related changes with no decline in fertility nor was it observed to develop any spontaneous neoplasm [Buffenstein:2008], the naked mole rat dies still of old age

Ageing within a population is not uniform either. There is a genetic heterogeneity as well as environmental influences that lead to a profile of different lifespans.

The ageing process within a single organism can be altered. In particular the genetic makeup and epigenetic modifications play an important roles, i.e. genes and their activities affect the ageing process. A variety of alterations in specific genes can extend lifespan quite substantially in model organisms and under laboratory conditions. Those increases are dramatic in simple budding yeast and nematodes, less so in fruit flies and less again in rodents.

Manipulating just single genes can accelerate ageing or slow down ageing hence greatly extend lifespan like up to 10-fold [Shmookler_Reis+Al:2009]. It has been demonstrated that it is possible to reverse ageing, even by simple ectopic overexpression of just single transcription factor out of two (IME1 and NDT80) in a model organism such as Saccharomyces cerevisiae [Unal+Al:2011]. In humans single gene mutations can lead to accelerated ageing (progeroid syndromes). On the other hand, many genetic differences were found to be associated with longevity in centenarians and some in supercentenarians [Fortney+Al:2015].

Ageing genes appear to be extremely conserved across species. For example, the sirtuin family of genes has a significant effect on the lifespan in many organisms. Their effect seems to be strong in yeast [Kaeberlein+Al:1999] and nematodes [Tissenbaum+Guarente:2001], and weak in fruit flies [Rogina+Helfand:2004] and mice [Price+Al:2012]. Further a substantial number of non-genetic interventions including single compounds were found to affect ageing and extend lifespan [Vaiserman+Al:2017].

Ageing is a widespread and almost ubiquitous phenomenon that affects virtually all biological species. For species that age, ageing appears to affect most aspects of an organism in a negative manner and increases its probability of health problems and death with increasing age. Though people live longer today through medical and safety improvements, the ageing process itself still leads to age-related disabilities and causes increasing physical, psychological, and economic burdens. While ageing has been an inevitable phenomenon for centuries, it now becomes more and more of a problem that can be understood (by science) and solved (via technology). Not only could ageing be solved as a theoretical problem, but it could also be treated as a medical condition.

However, the precise mechanisms of ageing remain largely unknown. Despite advancements in understanding the mechanisms of ageing (from a "backwater" of biology, full of anecdotes, to a serious discipline) and the possibility to interfere with the ageing process by changing just a single gene, applying dietary interventions (even with a single type of molecule) [de_Magalhaes+Al:2012] or simply repairing the damage (via regenerative medicine), the actual evolutionary theory ("why") and molecular/physiological mechanism ("how") of ageing remains unknown. To understand the biology of ageing requires posing testable and reasonable questions like [Arking:2006]:

  • Why do even two closely related species have such very different lifespan, despite their huge physiological similarity?
  • What causes the deteriorative changes during the lifespan of each of these species?
  • Are the causes the same between various species or are they different?
  • Can deteriorative changes be postponed or even reversed?
  • Is it feasible to reliable predict individual lifespan?
  • Is it possible to prolong the lifespan of humans by utilizing insights from other species?

Some anti-ageing mechanisms are species-specific (private mechanisms), others appear to be highly conserved across phylogenetic lines (public mechanisms). In the latter case, insights obtained from investigations on one species of laboratory organism can be translated to rodents or to primates and perhaps humans. Although all ageing mechanisms are of particular interests, conserved mechanisms have the greatest significance because they may imply possible interventions into human ageing.

Biology does not deal only with mere facts, but rather with developing an understanding of underlying mechanisms. There are three types of evidence [Arking:2006]:

  1. Correlative
  2. Loss-of-function
  3. Gain-of-function

Loss-of-function and gain-of-function are quite common approaches in genetics, while correlative evidence is dominating genomics. Correlative evidence is derived from observed temporal or spatial correlations between two or more events. Loss-of-function evidence is based on deactivation of an entity, e.g. the inactivation of a gene by knock-out or knock-down. Gain-of-function is the strongest type of evidence in which some technique is used to specifically increase the activity of an entity. All three types of evidence are used to infer causality among events, while it is challenging for correlative evidence, causation is more likely to be inferred from loss-of-function and especially gain-of-function data. However uncertainty of inference remains.

Cellular Senescence

Cellular senescence is an irreversible growth arrest that may be an evolved anti-tumour mechanism. Senescence is a natural mechanism restricting propagation of cells, which passed through genotoxic or oncogene stresses, by epigenetic reprogramming. It is a kind of program or a state, basically subroutine, which the cell adapts after damage, stress or some kind of damaging signal. Senescence is a general purpose mechanism that is used for repair systems. Cellular senescence prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing [Baker+Al:2016]. It is a primitive and very ancient process that even occurs in single cellular organism.

Cellular senescence is induced by short telomeres (replicative senescence), but it can also be induced by various stressors (stress-induced premature senescence). There are more than 50 oncogenic or mitogenic alterations that are able to induce senescence [Gorgoulis+Halazonetis:2010].

There are certain phenotypes associated with the state of cellular senescence such as obvious morphological changes. Senescence cells enlarge and become resistant to apoptosis. Cellular senescence is frequently characterized by the expression of the p16 protein. There is also the formation of senescence-associated heterochromatin foci.

Cellular senescence exhibits a distinctive secretory phenotype [Baker+Al:2016]. This associated secretion profile (Senescence-Associated Secretory Phenotype; SASP) of senescence cells depends on the type of insult. Senescence markers show already up during development. However senescence cells accumulate in various tissues/organs over time [Baker+Al:2016]. It is a growth arrest that for some reason occurs because either the cell is damaged or due to some regenerative response. The type of profile of secretion depends on the context of damage/triggering signalling.

It is commonly believed that cellular senescence underlies organismal senescence in mammals.

[Baker+Al:2016](1, 2, 3) Baker, Darren J; Childs, Bennett G; Durik, Matej; Wijers, Melinde E; Sieben, Cynthia J; Zhong, Jian; Saltness, Rachel A; Jeganathan, Karthik B; Verzosa, Grace Casaclang; Pezeshki, Abdulmohammad; Khazaie, Khashayarsha; Miller, Jordan D; & van Deursen, Jan M (2016). 'Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.' Nature. 530(7589), pp. 184-9.
[Gorgoulis+Halazonetis:2010]Gorgoulis, Vassilis G & Halazonetis, Thanos D (2010). 'Oncogene-induced senescence: the bright and dark side of the response.' Current opinion in cell biology. 22(6), pp. 816-27.

Mechanisms of Ageing

There are many possible mechanisms involved in ageing. Over the last decades, theories about ageing have emerged and faded. The true nature of the ageing process however, is still uncertain. What is exactly happening on a biochemical, genetic, and physiological level still remains to be understood. What we see in an ageing person is a great deal of change in appearance, a decline in overall fitness and an increased chance of getting age-related diseases. These are, however, only the visible sides of the changes that start at the molecular level, then the cellular level, then progress to the tissue and organ level until in the end the whole physiology is affected. What are these processes that result in ageing? Although ageing is undoubtedly complex, it may be regulated by common mechanisms that are simpler than the effects they produce [Arking:2006].

Defining ageing clearly is challenging. Our understanding of how and why we age will originate from the study of the processes that happen in the cell and observable biological markers of ageing.

References

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