What is aging? Theories of aging

Highlights:

• The principles of aging can be divided into evolutionary, molecular, genetic, and epigenetic
• Modern biological theories of aging are separated into programmed theories of aging and damage/error theories of aging
• There is no ultimate theory of aging and the theories are not mutually exclusive, and most likely, several processes contribute to how and why humans age

Introduction

Aging is a physiological process lead by biological and genetic pathways associated with lifespan and is a common cause of all age-related diseases. The research on aging biology is currently focused on unraveling the biochemical and genetic pathways that lead to aging. Some of the mechanisms standing behind aging have been identified and can be called the hallmarks of aging. These include genomic instability, telomere shortening, epigenetic alterations, or cellular senescence. Based on the Global Burden of Disease study done in 2017, 31.4 % of diseases are age-related, and the percentage rises with the country's wealth, reflecting that aging causes a significant burden on social and economic stability worldwide (1). 

The main principles of aging

Evolutionary aging 

The natural lifespan or time that the organism needs to fulfill the successful reproduction for the continuation of generations is called the essential lifespan. The principle is that the species that mature and reproduce quickly have a short essential lifespan, an example of which can be a week-long essential lifespan of a fruit fly. On the other hand, the slow maturation, late reproduction, and small reproductive potential usually pair with a long essential lifespan than in humans, as an example, lasts up to 50 years. The theory of evolution by Darwin says that random and heritable variation of biological traits between individuals leads to natural selection. It is the process of preferential reproduction of those individuals who are exceptionally fit in a given environment (2). The essential lifespan is the only time during which this genetic selection and functional optimization happen. Therefore aging, which increases vulnerability and ultimately leads to the death of organisms, is considered to manifest mainly during the period of extended survival beyond the essential lifespan (3). The evolutionary theory of aging suggests three main models for how aging evolves: 

• the theory of mutation accumulation – the power of natural selection lowers with age, making it possible for hazardous late-acting genes to exist, because there is no evolutionary mechanism to remove a population of mutations that cause harmful effects only in old animals.
• the disposable soma model - the organism has limited bulk of resources which can be used for cellular processes. If organisms invested in growth and reproduction, it would result in limited resources for DNA repair maintenance, leading to the development of all hallmarks of aging (4).
• the antagonistic pleiotropy hypothesis - aging evolves due to the pleiotropic effect of genes such as those beneficial early in life and then harmful at late ages (2).

Molecular aging

Molecular aging states three primary sources of damage within a cell that leads to aging. First, reactive oxygen species (ROS) and free radicals that are formed due to external inducers of damage and due to cellular metabolism involving oxygen, metals, and other metabolites. Second is the surplus of glucose and its metabolites and their biochemical interactions with reactive oxygen species. Lastly, we have random errors in biochemical processes, including DNA duplication, transcription, post-transcriptional processing, translation, and post-translational modifications (3).

Genetic aging

All molecular processes are based on and regulated by genes. Genes involved in the aging process are sometimes called gerontogenes, and their mutations can prolong or shorten the lifespan. An example could be human leukocyte antigen (HLA) and angiotensin-converting enzyme gene (ACE) polymorphisms observed in centenarians. The GenAge database now lists 307 human aging-related genes, and the LongevityMap database of human genetic association studies contains 550 results. Mutations of gernotogenes can cause premature aging syndromes (5). Studies have also reported a connection between human longevity and single nucleotide polymorphisms (SNP) in pathways, including heat shock response, mitochondrial functions, immune response, and cholesterol metabolism. An analysis of the various functions of the genes associated with aging and longevity shows that these genes cover a wide range of biochemical pathways, such as energy metabolism, kinase signaling, and transcription factor function (3).

Epigenetics of aging

Epigenetics studies heritable changes in gene function that do not involve changes in the DNA sequence. Epigenetic effects and alterations have substantial effects on health, survival, and aging. Most researched epigenetic markers of aging are DNA methylation such as cytosine 5-methylation, chromatin remodeling, and histone modifications such as lysine methylation and acetylation. All these epigenetic changes contribute to a loss of heterochromatin in aged cells (3, 5, 6).

Modern biological theories of aging

Theories of aging have been researched from many angles and could be separated into many fields. There are psychological theories of aging such as stage theories of human development or cognitive plasticity and cognitive reserve (7); evolutionary theories (partially described above), sociological and biological ones. The latest of which will be described in this article. Based on the commentary written by K. Jin in 2010 (8), the modern biological theories of aging can be divided into two main categories: programmed theories of aging and damage/error theories of aging. The programmed theories of aging state that aging is pre-programmed and follows a specific schedule – biological clock. Programmed theories of aging include:

• Programmed longevity theory - according to this theory, aging results from a sequential switching on and off of specific genes or genetic "longevity programs." It means that aging can be considered the result of the end or at least of a partial inactivation of a "longevity program" maintaining the youth of the organism (9). A version of programmed theory can be the telomere shortening in the cells. Telomeres are at the end of each chromosome, and with every cell division, they become shorter. After around 100 rounds of division, the telomere shortening or loss triggers the cell senescence (1). 

• Endocrine theory - the endocrine system impacts the control, communication, and maintenance of other systems within an organism and the ability of organisms to adapt to the environment in which they live. Aging is due to changes in endocrine functions of hypothalamus-pituitary gland-endocrine systems that are crucial for these processes. The hormonal pathways playing a crucial role in the hormonal regulation of aging are the insulin/IGF-1 signaling pathway, estrogen production in women, and melatonin secretion (10, 11).

• Immunological theory - the immune system declines over time, which increases susceptibility to infectious disease, and causes aging and death. The effectiveness of the immune system is the highest at puberty and gradually declines with age. The antibodies lose their effectiveness, and fewer new diseases can be combated effectively by the body, which causes cellular stress and eventual death. Aging deregulates the balance between pro- and anti-inflammatory components, promoting chronic inflammation and disease development (12, 13).

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The damage or error theories focus on environmental impact on living organisms that can induce cumulative cellular damage as a leading cause of aging, and they include theories such as:

• Wear and tear theory - cells and tissues wear out with time and cumulate damage which results in aging. Many types of cells and tissues such as heart muscle or neurons have no regenerative possibilities and would not be replaced when worn out. Damage to cells can be caused by accidents, radiation, toxins, and nutrition (13).

• Rate of living theory - the more significant an organism's rate of oxygen basal metabolism or energy expenditure, the shorter the lifespan. This theory explains the longevity effects of calorie restriction (8, 13). 
  

• Cross-linking theory - according to this theory, with time, bonds between molecules such as proteins start to occur that are generally not connected. The cross-linking occurs in collagen proteins which show as wrinkles on the skin. Cross-linked proteins also cause senile cataracts (14). 
  

• Free radicals theory - Aging-causing oxidative damage accumulation is introduced to organisms by free radicals produced in oxidative metabolism such as superoxide O2- and hydroxyl OH- anions, nitric oxide NO or peroxynitrite ONOO-. Free radicals cause DNA damage and modifications and lipid oxidation and damage in cell membranes (13, 15).
  

• Somatic DNA damage theory - DNA damages happen every day in cells of living organisms. Most of these damages are repaired, but they can accumulate too, especially in non-dividing cells. The prevalence of genetic mutations increases with age and causes cell deterioration and loss of function (8).
  

There are more theories of aging, and they are constantly being researched and changed. Examples of those could be:

• Error catastrophe theory – protein synthesis is possible thanks to mechanisms of replication of the DNA, transcription, and translation. There might be errors occurring at each step, causing faulty genes, mRNA, and proteins production. Faulty proteins then cause the cells to malfunction. The cells repair system eliminates such errors, but there are exceptions and risks of errors even in those repair systems that lead to errors accumulation or error catastrophe.
  

• Mitochondrial theory – the DNA in mitochondria is under constant impact of free radicals, and simultaneously mitochondria lack DNA repair enzymes. Because of that, mitochondrial DNA is prone to damage from external toxic molecules and radioactivity. The damaged mitochondrial DNA leads to a decrease in energy production by reducing ATP generation, an increase of free radical production, and in return, mitochondria degradation (13).

There is no ultimate theory of aging

Most clinicians agree that aging increases the incidence of diseases such as Alzheimer's disease. However, scientists have already proven that mutations that slow aging can postpone such diseases in simple organisms. Understanding the aging process seems like the key to future age-related disease prevention. However, despite more than 300 general aging theories, no single theory thoroughly explains aging, which is complex and multifactorial. The numerous aging theories are not necessarily mutually exclusive, and most likely, several processes contribute to how and why humans age. Also, some mechanisms likely contribute to different degrees in different individuals (15).

References

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8.            Jin K. Modern Biological Theories of Aging. Aging Dis. 2010;1(2):72-4.

9.            Longo VD. Programmed longevity, youthspan, and juventology. Aging Cell. 2019;18(1):e12843.

10.          Weinert BT, Timiras PS. Invited review: Theories of aging. Journal of applied physiology. 2003;95(4):1706-16.

11.          Fabris N. A neuroendocrine-immune theory of aging. Int J Neurosci. 1990;51(3-4):373-5.

12.          Sergiev PV, Dontsova OA, Berezkin GV. Theories of aging: an ever-evolving field. Acta Naturae. 2015;7(1):9-18.

13.          Park DC, Yeo SG. Aging. Korean J Audiol. 2013;17(2):39-44.

14.          Bjorksten J, Tenhu H. The crosslinking theory of aging—Added evidence. Experimental gerontology. 1990;25(2):91-5.

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