As human life expectancy increases, aging has become a global issue. As aging, the body's tissues, organs, and systems gradually lose their function and elasticity. Our body becomes increasingly fragile and prone to damage, significantly increasing the risk of disease. Aging is a complex biological process that can be observed from multiple levels, including molecular, cellular, and systemic. Cellular aging, as the basis of overall aging, is crucial for delaying the aging process.
What is aging?
Aging is a complex physiological process. The World Health Organization (WHO) defines it as irreversible, progressive, and universal multi-system organ function decline. By 2030, one-sixth of the global population will be aged 60 or over. The proportion of people aged 60 and over will increase from 1 billion in 2020 to 1.4 billion. By 2050, the global population aged 60 and over will double to 2.1 billion. It is estimated that between 2020 and 2050, the number of people aged 80 and over will double to reach 426 million[1].
The visible signs of human aging include wrinkles, bone loss, decreased memory, and an increase in chronic diseases, all of which lower the quality of life[2]. Anti-aging not only means finding ways to prolong life but also aims to pursue a healthier life. With the exacerbation of population aging, this demand will become a global challenge, as people hope to maintain healthy, youthful bodies.
How does the concept of aging evolve?
Throughout history, people have been fascinated by the process of combating aging. From ancient Chinese medicine to modern scientific research, efforts have been made to understand and address the aging problem, resulting in a series of anti-aging solutions.
Historically, literature on longevity is generally divided into two main periods: the first period from the 16th to the 18th century, and the second period from the 19th century to the early 20th century. Although advocates of both periods considered the elimination of age-related diseases as a core goal, they differed significantly in their descriptions of life stages and ultimate goals[3].
During the Renaissance, the concept of longevity arose from the belief that individuals could control the length and quality of life, often using religious and mythological ideas to achieve immortality or extreme longevity. One of the most influential advocates was the Italian nobleman Luigi Cornaro, whose work "The Art of Living Long" written in 1550 became the Bible of longevity advocates. Cornaro believed that the cause of aging was a significant decline in vitality, and maintaining vitality was the key to longevity. He believed that longevity could be achieved through moderation and a simple life. He did not consider old age itself as an "enemy" but rather as a stage of life with unique significance, a concept supported by Enlightenment philosophers.
However, since the 19th century, the concept has been challenged with the development of science, and scientists have regarded aging as a hateful and fearful disease. In contrast, advocates of this period tended to emphasize prolonging health and improving age-related diseases and disabilities. Their goal was to prolong the "middle-aged" period of life rather than achieve immortality. Pioneering research at the Paris Hospital tracked tissue lesions and observed changes in cells, concluding that aging is not just physical decline and cannot be easily controlled through diet or exercise. Subsequent medical researchers also found an inseparable connection between old age and disease, as stated by the father of geriatrics, Ignatz Leo Nascher "It is impossible to draw a clear line between old age and disease." With the appearance of early signs of aging, such as short-term memory loss or slowed gait, people began to see old age as a debilitating disease.
Scientific development makes people gradually realize that although immortality cannot be achieved, scientific anti-aging solutions can help weaken the link between aging and disease. At its most basic level, delaying aging from the source is essential, and the concept of cellular anti-aging has emerged.
How Does Cellular Aging transform into Overall Aging?
We can understand this relationship from both microscopic and macroscopic levels. Cells are the basic units of organisms and the foundation of organs and tissues. Healthy cells can provide sufficient energy to support the normal functioning of various body functions[4]. However, during prolonged physiological activity and division processes, cells undergo a series of metabolic and repair processes, leading to the degradation and damage of their functions. The accumulation of aging cells ultimately develops into overall aging[5-6].
Cellular aging is usually accompanied by the production of senescence-associated secretory phenotype (SASP), which acts on cells in the local microenvironment, altering the biological behavior of neighboring cells. SASP contains various pro-inflammatory molecules, and chronic inflammation is often attributed to the development of SASP in the body. These microscopic molecules secreted by aging cells are major risk factors for various age-related diseases, including but not limited to malignant tumors[7-9].
Typically, the inflammation produced by aging cells is sufficient to activate the immune system to clear aging cells within days or weeks. However, according to the threshold theory of senescent cell burden, once the abundance of aging cells reaches a threshold, the immune system cannot keep up with clearing them. In turn, immune system cells also become senescent, further exacerbating the accumulation of aging cells. These continuously accumulating aging cells gradually lose vitality and function, causing tissue and organ degeneration at the macroscopic level, ultimately leading to the appearance of various forms of diseases and aging[10].
Threshold theory of aging cell accumulation [10]
Aging is the basis of many chronic diseases, such as neurodegenerative diseases, heart disease, and cancer. To better understand and intervene in the aging process, scientists have conducted extensive research for decades, revealing 12 fundamental aging markers, known as "hallmarks of aging," which are almost the root causes of all age-related diseases[11]. Most of these 12 markers involve the cellular level, including genomic instability, cellular environmental imbalance, etc. It can be said that cellular aging is the "culprit" of aging, and the importance of combating aging at the cellular level is self-evident. By understanding these hallmarks, we can seek methods to intervene in the cellular aging process, thereby delaying the progression of overall aging.
(Carlos Lo´pez-Otı´n et al., 2022, Cell) 12 hallmarks of aging: Most of these markers involve changes in cells under aging conditions, such as the structure and function of intracellular, cellular aging and depletion, cell-to-cell communication, and changes in cellular secretions. In addition, these determinants of aging are also closely related to the health characteristics of the organism, including spatially zoned tissue characteristics, maintaining internal environmental homeostasis, and a series of responses to disturbances. Overall, these findings suggest that the overall aging at the macroscopic level is closely associated with the cellular state at the microscopic level. [11]
Internal and External Factors of Cellular Aging
The mechanisms of cellular aging are still under various hypotheses.
Internal factors
a) The genetic determinism believes that aging is a genetic programmed process, and the driving force and determinant are the genetic genome; genes that control growth, development, and aging are orderly turned on and off at specific times.
b) The free radical theory of aging holds that reactive oxygen species cause cellular damage and aging. Under normal conditions, the production of free radicals in the body has two aspects: one is exogenous free radicals caused by high temperature, radiation, photolysis, chemical substances, etc.; the other is endogenous free radicals generated by various metabolic reactions in the body.
c) The telomere clock theory believes that telomeres shorten with cell division as the main cause of aging. Under normal circumstances, with the continuous division of cells, the special structure at the end of chromosomes, "telomeres," gradually shorten. When telomeres shorten to a certain extent, cell proliferation stops, and cellular aging occurs.
d) Accumulation of cellular metabolic waste can cause cellular aging. This theory refers to the accumulation of metabolic waste due to the decline in cellular function. On the one hand, cells cannot timely excrete metabolic waste, and on the other hand, they cannot degrade and digest them, resulting in the accumulation of more and more metabolic waste. These accumulated waste substances occupy more and more space in the cell, affecting the transport of cellular metabolic waste, thus hindering the normal physiological function of the cell, eventually leading to cell aging. (Such as lipofuscin deposition)
e) Genetic transcription or translation errors lead to cellular aging. With age, the efficiency of DNA replication in the body's cells decreases, and errors in the synthesis of large molecules such as nucleic acids, proteins, and enzymes often occur. This gradually accumulated error ultimately leads to a decrease in cellular function, gradual cellular aging, and death.
External factors
Although cellular aging is an inevitable physiological process, many external factors can accelerate this process:
a) Diseases and medications: Disease development and medication use may disrupt the balance between the formation and clearance of aging cells, thereby accelerating cellular aging. A typical example is that cancer patients undergoing chemotherapy induce cellular aging in normal tissues and trigger pro-inflammatory stress responses, leading to a series of adverse reactions such as fatigue, cancer recurrence, and metastasis.
b) Social stress and anxiety: Prolonged social stress and anxiety can produce hormones and oxidative stress substances, which negatively affect cells. These stresses can disrupt the internal balance of cells, leading to abnormal cell function and accelerating cellular aging.
c) Lifestyle habits: Poor lifestyle habits, such as unhealthy diet, lack of exercise, and irregular sleep, may also accelerate cellular aging. Unhealthy eating habits and lack of exercise can cause chronic inflammation and oxidative stress, while irregular sleep can disrupt the body's biological clock, affecting normal cell function.
d) Environmental pollution: Pollution of natural environments such as air and soil can also accelerate cellular aging. Pollutants can cause oxidative stress and inflammatory responses, damaging cells. Long-term exposure to environmental pollution can have negative effects on cell health, accelerating the process of cellular aging.
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