Review of anti-aging research

1.Evolutionary Perspectives

Evolutionary Level Theories  Charles Darwin's theory of evolution suggests that organisms undergo genetic mutations, and in the process of survival, individuals with advantageous variations can survive and reproduce, while those with disadvantageous variations are gradually eliminated. This concept is known as "survival of the fittest." Evolutionary theories related to aging include the Mutation Accumulation Theory, Disposable Soma Theory, and Antagonistic Pleiotropy Theory.

In 1952, Peter Medawar proposed the Mutation Accumulation Theory of aging, which suggests that harmful late-life mutations can accumulate within a population, ultimately leading to pathology and aging. The direction of genetic mutations can be either good or bad. Harmful pre-reproductive mutations are naturally selected out through human reproduction, but post-reproductive harmful mutations cannot be eliminated, preventing humans from achieving eternal youth.

In the 1980s, scientists introduced the Disposable Soma Theory, which suggests that organisms must balance their energy resources between reproduction and maintaining their soma (body). The body's cells can be divided into soma cells responsible for maintaining body functions and germ cells responsible for reproduction. If the energy expenditure for a single reproductive event is too high, organisms tend to invest their energy in a single reproductive event to produce a larger number of offspring. On the other hand, if organisms have opportunities for subsequent reproductive events, they will allocate more energy to maintaining their own survival. Humans, with their extended reproductive period, fall into this category.

2. Cellular Perspectives

Free Radical Theory  In 1965, Denham Harman proposed the Free Radical Theory of aging, which suggests that aging is the result of cumulative oxidative damage to cellular components caused by free radical reactions. Free radicals, primarily derived from mitochondria, accumulate with age, leading to mitochondrial damage, affecting energy metabolism, and causing increased electron leakage and further free radical generation, creating a vicious cycle.

Telomere Theory In 1961, anatomists Leonard Hayflick and Paul Moorhead, through a series of experiments, concluded that the division of most normal cells is limited. This limit is known as the Hayflick limit. The reason for the limited cell division is related to cellular aging due to the way DNA replicates. Telomeres are repetitive DNA sequences located at the ends of chromosomes, crucial for maintaining genetic information integrity. During DNA replication, telomeres are shortened. As cells continue to divide, telomeres become increasingly shorter. When cell division reaches 40-60 times, telomeres become very short, and the DNA repair mechanism recognizes them as damaged DNA, activating cellular pathways that halt the cell cycle, preventing further division. This phenomenon of telomere shortening during cell division, leading to reduced cell division capacity, is known as cellular replicative aging.

Cellular aging can lead to cellular dysfunction, increased resistance to apoptosis, and increased secretion of inflammatory factors, ultimately causing negative effects on the organism and contributing to the overall aging process.

3. Molecular Perspectives

Genetic Regulation Theory Aging is the result of changes in gene expression. Many genes show altered expression patterns with age, but these selective changes are unlikely to act directly on genes that promote aging. Rather, the impact of genes that promote longevity seems to be more substantial.

Research on centenarians and their relatives has revealed a critical genetic factor that contributes to a longer lifespan. In one study, siblings of centenarians showed an average death rate that was half of the average death rate for the 1900 U.S. population. This sustained reduction in lifetime death rates implies a genetic rather than environmental or socioeconomic influence. A genetic locus on chromosome 4 may contain genes that promote longevity, suggesting a hereditary component to specific lifespans.

Somatic Cell Mutation Theory The Somatic Cell Mutation Theory suggests that mutations leading to cellular morphological changes, functional impairment, or loss are significant contributors to human aging. When both alleles on two homologous chromosomes are affected by mutation factors in diploid cells, the offspring cells will quickly experience changes in form and function or even die. The aging changes in diploid cells depend on the ratio of alleles affected and the level of defects caused.

1.3.3 Biomolecular Cross-Linking Theory

The fundamental cause of biological aging is progressive molecular cross-linking resulting from the interaction of chemically reactive groups in various biomolecules. It posits that living organisms are unstable chemical systems, functioning as dissipative structures. Biomolecules within the system possess numerous chemically reactive groups, which inevitably interact and undergo chemical reactions, leading to the slow cross-linking of biomolecules. As time progresses, the accumulation of these changes causes biological tissues to gradually exhibit aging. These molecular changes can affect the activity of genes by causing changes in the DNA. On one hand, these changes may express different activities or even change the effects of genes. On the other hand, they can affect the recognition and binding of RNA polymerases, thereby affecting transcriptional activity, causing a gradual loss of gene transcription activity and resulting in progressive and regular phenotypic changes and aging.

4.System-Level Perspectives

Endocrine Disruption Theory Aging is due to the deterioration of neuroendocrine functions, which selectively affect neural and hormonal regulation of functions crucial for evolution, such as reproduction, growth, development, and responses to stress. An important aspect of this theory is the perception by the organism of the hypothalamic-pituitary-adrenal (HPA) axis as the "pacemaker" that signals the onset and termination of each phase of life. With aging and the response to continued and severe stress, both feedback mechanisms may be damaged, and the glucocorticoids themselves may be neurotoxic to neurons, thereby disrupting feedback control and hormonal rhythmicity.

Immune Function Degradation Theory The immune system must be capable of controlling and eliminating foreign organisms and substances within the host while recognizing and avoiding the destruction of self-molecules (cells and tissues). Different aspects of the immune response are affected to varying degrees with age. The number of T cells, B cells, and NK cells decreases with aging, but mast cells and dendritic cells involved in inflammatory reactions increase. Immune system degradation results in an inability to effectively clear aging cells, leading to chronic inflammation, promoting cellular aging, and ultimately contributing to tissue aging and impairing organ function.