Aging is an inevitable natural phenomenon that involves multiple mechanisms in the human body. In simpler terms, it is the process of becoming older. Unlike many organisms present in nature such as fungi or bacteria which are potentially biologically immortal, humans do not have the capacity to maintain life or youth forever. In a molecular level, aging refers to cells within an organism which have stopped dividing which is termed as cellular senescence.

Aging involves accumulation of changes in humans throughout time. These changes involve physical, psychological, and sociocultural changes. Moreover, aging is the most common and greatest known risk factor for the development of human diseases, which about two thirds of the world population are at risk for age-related cause of death.

There are several different theories on the causes of aging. However, up until today, aging still remains a mystery in science. There are a lot of different theories that discuss how and what are the causes of aging. Most theories link aging with DNA damage. DNA is the main component of the human cells which basically directs all components of life. The accumulation of damage to the DNA causes for biological systems to halt and fail. Aging is also linked to the internal process such as DNA methylation which causes change to the activity of a DNA segment without changing its sequence, resulting in repressing the gene transcription. Both of these activities can lead to the natural process of aging.

Theories on Aging

As slightly presented above, there are multiple theories of aging. In order to understand how humans can slow down the natural process of aging, it is important to discuss what these specific theories are and how such processes affect cells, tissues, and organs that lead to aging. 

  • Free Radical Theory of Aging

The free radical theory of aging was first presented by Harman in the early 1950’s. He postulated that the accumulation of free oxygen radicals in cells is responsible for cell aging and death of all living organisms. During 1972, the mitochondria which is the organelle of the cell responsible for the initiation of most of the free radical reactions, was discovered. This discovery led to the revision of the theory which now states that the life span of an organism is directly proportional to the rate of free radical damage to the mitochondria. Moreover, the increasing age-related oxidative stress is a consequence of the imbalance between the free radical production and antioxidant defenses, with predilection to the production of the former. 

Furthermore, because all organisms including humans live in an environment that have wide and different sources of reactive oxygen species, aging is inevitable. The basis of energy production in humans is through mitochondrial respiration which by itself generates reactive oxygen species. Hence, the ubiquitous nature of oxidative free radicals, and perhaps of the free radical theory of aging, is proposed by the presence of superoxide dismutase in all aerobic organisms and in charge of scavenging superoxide anions. 

Finally, the free radical theory of aging is divided into a number of different hypotheses which explain the role of oxidative stress to particular organelles of cells and types of damaged molecules in the aging process. One of the hypotheses states that altered enzyme are introduced to the electron transport chain through the mutations in mitochondrial DNA which in the end promote free radical damage. This also results in increased free radical leakage and mitochondrial DNA mutation which then cause for increased oxidant production. This cycle finally leads to cellular or organ failure, and aging. Another well known hypothesis under the free radical theory of aging states that free radicals cause aging because of the accumulation of oxidized proteins in cells. The reduced capacity to clear these oxidized proteins in cells due to natural aging may be responsible for the build-up of damaged, dysfunctional molecules in the cell. 

  • Mitochondrial Theory of Aging

The mitochondrial theory of aging is often considered as an extension and refinement of the free radical theory. As stated above, mitochondria is the main organelle for cellular respiration which also produces free radicals along the process. Moreover, theories of aging explore mechanisms that focus on DNA. In mammalian cells, mitochondria and the nucleus are the only organelles possessing DNA. Mitochondrial DNA, even only comprising 1% to 3% of genetic material  in humans, is a sensitive target for oxygen radical attack because it lies close proximity to the sites of oxygen radical production. Studies have shown that the level of oxidatively oxidized bases in mitochondrial DNA is 10- to 20-fold higher than that in nuclear DNA. Moreover, mutations in mitochondrial DNA accumulate progressively during life. These mutations are directly responsible for a measurable deficiency in cellular oxidative phosphorylation activity which then leads to an increased reactive oxygen species production. These mutations also affect the entire electron transfer chain which potentially alters both the assembly and function of the products of numerous nuclear genes in electron transfer chain complexes. This alteration and defects in the electron transfer chain can have degenerative effects in the entire cellular energetics. Both of these processes result in an increased rate of mitochondrial DNA damage and mutagenesis, and oxidative damage and dysfunction, which ultimately cause cell death. This proves the vital importance of the mitochondria in the aging process and in determining longevity. It is also important to note that studies show that exposure to different environmental toxins and pollution may lead to a progressive accumulation of mitochondrial DNA damage which then accelerate aging.

  • Gene Regulation Theory of Aging

The gene regulation theory of aging states that aging is the results of several and multiple changes occurring in the gene expression. Today, evidence in this field still remains controversial, and rather than looking at aging as a programmed mechanism directly governed by genes, it should be more safely considered as a stochastic and natural process. Aging is accompanied by some loss of tissue function, which is at least partially due to either the age-related loss of cells from the tissue or an increased proportion of dysfunctional cells. Moreover, even with recent development, it is still unknown how the proteins coded by these regulatory genes are acting in the regulation of longevity and aging. Other studies conducted have found out that genes assumed to be involved in aging are not able to reverse or stop the relentless expression of the molecular disorder that is the hallmark of aging. More importantly this theory remains very important because if it will be confirmed that changes in gene expression can modulate the aging process, it can then be used to develop interventions aimed at delaying aging. Such interventions include gene manipulations possible that may have limited potential for direct application in humans or, the potential for improving and developing cell replacement therapy in reversing some of the adverse effects of aging. 

  • Telomere Regulation of Aging

Telomeres are specialized DNA sequences found at the ends of the chromosomes. In humans, these are composed of repeating sequences of TTAGGG reiterated in tandems. These telomere sequences stabilize the chromosomal ends through binding to proteins that prevent them for disintegration. Because with each cell division there is a small amount of DNA that is necessarily lost at each chromosome end, resulting in shorter telomeres and altered telomere structure, this process leads to the cessation of cellular proliferation and thus cellular aging. 

Telomerase is responsible for the synthesis of the telomeres and thus responsible for maintaining the lengths of the chromosomes. This enzyme adds telomere repeats to the ends of the chromosome. Hence, the expression of this enzyme is important for cellular life and even cellular immortalization. Findings have shown that decrease or absence of telomerase enzyme is a fundamental basis for cellular aging. Studies proved that aging occurs due to shortening of the telomeres with each cell division and that there is a direct relationship between the presence of telomerase enzyme, chromosomal stability, and mortality of cells. These findings have led to further research in cellular aging and how telomerase can maintain a youthful state and act as a potential “anti-aging” medium. 

  • Immune Theory of Aging

This immune theory of aging or network theory of aging proposed by Franceschi in 1989 suggests that aging is indirectly controlled by a network of cellular and cell defense mechanisms. DNA repair enzymes, ADP-ribosyl polymerase, enzymatic and non-enzymatic antioxidant systems such as superoxide dismutase, catalase, glutathione peroxidase, and production of heat shock proteins are the major parts of this network system. These mechanisms function to reduce the negative effects of a wide range of different physical, chemical, and biological stressors. The efficiency of the network is genetically controlled and differs between individuals, explaining in this way the observed differences in lifespan in humans. Moreover, in the network theory of aging, the immune system serves as the most powerful mechanism to face stressors.  In particular, the macrophage has been suggested as the primary regulator of the relationship between innate immunity, inflammation and stress. The subclinical chronic inflammatory status characterizing older persons and the probable features of the aging process can be explained through the macrophage activation secondary to chronic stress. Moreover,  the progressive age-related antigenic stress causes the lymphocytes to be affected which results in a chronic stimulation responsible for the expansion of memory cells, the reduction of naïve immune cells, and the decrease in the T-cell supply. Hence, reduction of these protective mechanisms against stressors may be one of the underlying causes of cellular aging. 

Age-related Physiological Changes

Now that the different and possible causes of aging have been presented above, it is important to note the different physical and biochemical age-related changes in the human organ systems for anti-aging strategies can be directed against them in order to control and improve these changes.