Cellular Aging and Age-Related Illness

Edward Bullmore explores the strong connection between inflammation and mental illness in his book, The Inflamed Mind. The book discusses several key points, including the role of the immune system in causing inflammation, the impact of stress on inflammation levels, and the potential use of anti-inflammatory drugs as a treatment for mental health disorders. The book suggests that targeting inflammation may lead to the development of new treatments for mental illnesses, such as depression ^[1].

Over 60 years ago, Leonard Hayflick observed that primary cells, which have undergone differentiation, have limited potential for proliferation in culture dishes. The phenomenon was named the Hayflick limit. The main reason for this limitation is the lack of an enzyme capable of repairing the shortening of telomeres, a segment of DNA. Telomeres are located at the end of each chromosome, and they shorten with each round of cell division. There is a threshold for the length of telomeres, and once this threshold is exceeded, cell division is prevented. Subsequent research has revealed that this phenomenon is not simply the inhibition of cell division. These cells display a unique senescence-associated secretory phenotype (SASP), altered metabolism, and impaired functions. The term cellular senescence was coined to describe these cells that have stopped dividing and entered the particular secretory phase.

During the secretory phase, various factors are released by senescent cells, with pro-inflammatory factors being the main ones. The primary physiological function of SASP is to attract immune cells that remove senescent cells. However, prolonged release of these factors may lead to various pathological conditions.

Senescence is a mechanism that prevents cells from multiplying when they are exposed to DNA damage, oncogene activation, oxidative stress, metabolic stressors, or pathogenic infections. Most of these stresses predispose cells to cancer. Therefore, senescence is primarily a physiological process that prevents cancer formation. However, if senescent cells are not eliminated and continue to amass over time, this healthy mechanism may become pathogenic. Senescent cell accumulation is seen in metabolic illnesses, such as obesity, and during the aging process. Chronic senescent cell accumulation has been linked to age-related problems such as diabetes, cardiovascular disease, neurological and mental disorders, and cancer ^[2].

Prolonged SASP is the prime suspect for the deleterious effects of cumulative senescence. Senescent cell accumulation may be caused by impaired immunological function and a deficiency in senescent cell removal. Also, the senescence of immune cells could potentially affect the immune system's ability to eliminate senescent cells independently. It is interesting that senescent cells, like zombie cells, can transfer their characteristic to normal cells via SASP. An increase in the number of senescent cells may trigger senescence in immune cells, and vice versa. It is unknown whether immunosenescence or non-immune cell senescence occurs first.

Senescence in peripheral tissues may affect the central nervous system through the secretion of SASP, which can cross the blood-brain barrier. Chronic senescence in brain cells, including neurons, astrocytes, microglia, oligodendrocytes, and other stromal cells, can have a deleterious effect. It is possible that peripheral inflammation, which has an impact on cognition and the brain, as discussed in The Inflamed Mind is caused by SASP components that have entered the CNS.

It has been shown that inflammation plays a role in depression, particularly in elderly people. While inflammation is a natural response of the body to injury or infection, chronic inflammation can lead to a range of mental health problems, including depression and fatigue, as well as peripheral non-communicable diseases. The studies suggest that inflammation can impact the brain and disrupt the production of neurotransmitters, leading to symptoms of depression.

A recent study investigated the correlation between late-life depression and molecular senescence markers. According to the study, individuals who suffer from depression in later life showed elevated levels of these markers, which can accelerate cellular aging and cause harm. The study also identified specific clinical characteristics and treatment outcomes that were associated with these indicators of senescence. This study highlights the importance of understanding the molecular pathways that contribute to late-life depression. Such understanding is crucial for developing more precise and effective treatments ^[3].

Targeting senescence could be a beneficial strategy for treating cognitive issues, particularly in older individuals, as it may have a positive impact on both mood and cognitive abilities. Senotherapeutic drugs are a novel class of medications that aim to eliminate or inhibit these cells. The development of senotherapeutic medicines and their translation from laboratory investigations to clinical trials is a hot topic in recent research. The potential advantages of these medications include treating numerous age-related disorders and extending healthy life. Senescent cells are resistant to physiological signals of death and immune responses. Dasatinib, Quercetin, Fisetin, and Navitoclax are drugs that specifically kill senescent cells and are recognized as senolytic drugs. On the other hand, senomorphic drugs inhibit the production of SASP and subsequent inflammation. Therefore, it seems that senotherapeutic medications may have beneficial effects on mental health disorders, particularly in elderly individuals ^[4].

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Recent findings suggest a link between senescence and age-related mental illnesses, such as depression, anxiety, and Alzheimer's. These studies suggest that the current approach to treating mental illness is overly focused on the brain while neglecting the crucial role of cellular senescence, immune response, and inflammation. It is important to emphasize the need for a more comprehensive approach to treating mental illness. The new findings suggest that senescence and systemic inflammation should be considered crucial elements in the development of innovative therapies such as senotherapeutic drugs.