Cellular anti-aging refers to the process of slowing down cell aging and delaying the overall aging of the body by regulating biological processes both inside and outside the cell. The research field of cellular anti-aging involves multiple disciplines such as molecular biology, cell biology, and genetics. Its goal is to find methods to extend cell lifespan and maintain cell function to improve the overall health of the organism.
How to achieve anti-aging at cellular level?
Currently, there are two main approaches to promote cell health. The first approach focuses on Senolytics, which directly eliminates aging cells, while the second approach targets inhibiting the formation of aging cells.
Senolytics, a combination of the words "seno" (senescent) and "lytic" (destroying), emerged as a mainstream product in the field of cellular anti-aging following a study in 2015 by scientist James L. Kirkland and colleagues [12]. Their research demonstrated that specific drugs or compounds (Senolytics) could eliminate senescent cells, reducing their negative impact on tissue function, delaying the aging process, and even improving certain age-related diseases. The physiological basis of this research lies in the fact that under normal circumstances, the body eliminates aging, damaged, and abnormal cells through apoptosis to maintain tissue and organ health. However, aging cells activate anti-apoptotic pathways, protecting themselves from apoptosis. Senolytic drugs selectively eliminate aging cells by inhibiting these pathways. Although the medical application of Senolytics is still in the research stage, it has shown potential therapeutic effects. In the long term, Senolytics may be used to treat various age-related diseases such as cardiovascular diseases, diabetes, cancer, arthritis, etc., potentially improving human life quality and health [13].
The other mainstream approach to cellular anti-aging targets the control factors of cellular aging, inhibiting the formation of aging cells and cellular functional decline from the source, thus maintaining cellular "youthfulness." [11]
Means of targeting celluar aging
|
Factors Affect Cellular Aging |
Causes |
Effects |
Targeted Approach |
|
Genomic instability |
Accumulation of DNA damage and mutations, affecting cell function |
Increases the risk of cells aging or developing cancer |
Enhance DNA repair mechanisms by increasing levels of SIRT6[14] and BubR1[15] |
|
Telomere attrition |
Telomeres gradually shorten with cell division |
Limits cell replication capacity and lifespan, leading to cellular aging and functional impairment |
Activate telomerase, such as Ergothioneine[16], to elongate telomeres, maintaining cell replication capacity |
|
Epigenetic alterations |
Changes in DNA methylation and histone modification patterns |
Cause dysregulation of gene expression, affecting cell function and aging process |
ntervene in epigenetic modifications, such as supplementing α-ketoglutarate to delay epigenetic clock progression [17] |
|
Proteostasis loss |
Accumulation of misfolded proteins and protein aggregates |
Interfere with normal protein function inside the cell, leading to cellular stress and aging |
Enhance protein quality control, such as using 4-phenylbutyrate to improve protein folding and degradation mechanisms, reducing endoplasmic reticulum stress [18] |
|
Impaired autophagy |
Decreased ability of cells to clear damaged organelles and protein aggregates |
Results in intracellular waste accumulation, promoting cellular aging |
Activate autophagy process, such as using Spermidine to clear intracellular waste [19] |
|
Nutrient sensing dysregulation |
Imbalance in cell sensing and metabolic regulation of nutrients |
Results in metabolic disorders, affecting cell growth and survival |
Reduce calorie intake or use growth hormone receptor antagonists to improve metabolic health [20] |
|
Mitochondrial dysfunction |
Imbalance in mitochondrial energy metabolism and ROS production |
Results in inadequate energy supply and increased oxidative stress, promoting cellular aging |
Compounds like TPP-thiazole [21], Salidroside [22], or Urolithin A [23] improve mitochondrial metabolism, reduce ROS production, and enhance energy efficiency |
|
Chronic inflammation |
External pathogen infections and disruption of internal homeostasis |
Continuous low-grade inflammation is associated with the development of various age-related diseases |
Blocking pro-inflammatory factors like TNF-α can prevent inflammation [24] |
Cellular aging and supplements
Although significant progress has been made in researching ways to combat aging at the cellular level, aging is a complex process that must be considered holistically. A considerable amount of theoretical research suggests that the mechanisms involved in aging are multifactorial, and the interdependence between aging characteristics means that strengthening or attenuating one characteristic often affects others. This emphasizes the fact that anti-aging strategies targeting individual hallmarks may not be effective. Therefore, targeting multiple aging hallmarks simultaneously may potentially enable the control of the aging process. A typical example is NAD+ precursors. NAD+ (Nicotinamide adenine dinucleotide) is an important coenzyme involved in various biological processes inside cells. The level of NAD+ decreases with age, affecting cellular metabolic health and function. Supplementing NAD+ precursors such as NMN and NR can increase intracellular NAD+ levels, exerting anti-aging effects by regulating multiple cellular aging pathways, including energy metabolism, Sirtuins proteins, oxidative stress, DNA repair, etc. The effectiveness of this approach has been recognized by a wide consumer base. [26]
Similarly, another emerging anti-aging star, fisetin, was frequently mentioned at longevity forums such as the CHL Conference 2024 (Unlock Healthy Longevity: Supplements, National University of Singapore) and the Supplyside West Exhibition. Fisetin, a potential player in the anti-aging field, indicated by the findings of Dr. Kirkland and colleagues at the Mayo Clinic in 2017. This research demonstrated fisetin's ability to act as a Senolytic, and due to its safety profile, researchers believe it may be a better candidate for eventual clinical interventions. Further research in 2018 found that fisetin's effect on senolytics surpasses previously well-known substances like quercetin, resveratrol, and curcumin. Recent studies have also revealed the signaling pathway involved in fisetin, including induction of autophagy (such as activating mitochondrial autophagy to clear oxidative mitochondria, maintaining a healthy mitochondrial environment), anti-inflammatory effects (including reducing the secretion of SASP by senescent cells), reducing oxidative stress, increasing SIRT family protein expression, promoting genomic stability, and other key factors controlling cellular aging [30-35]. These findings suggest that besides directly clearing aging cells as a Senolytic, fisetin may also have the potential to inhibit the formation of aging cells.
The comprehensive effects of fisetin support its prominent position in the field of cellular anti-aging. Apart from being used alone, fisetin can also be combined with other products. Taking NAD+ precursors as an example, it was mentioned earlier that the rapid decline in NAD+ levels with age can be attributed to the activation of CD38, an enzyme responsible for NAD+ degradation, which disrupts the synthesis pathway of NAD+ during aging. In fact, the underlying reason for the decline in NAD+ and the increase in CD38 may be the accumulation of aging cells [36]. The SASP secreted by aging cells has inflammatory characteristics, promoting the formation of M1 macrophages, which typically express a large amount of CD38, further exacerbating the consumption of NAD+. Mechanistically, the combination of fisetin with NR/NMN, on the one hand, directly supplements NAD+ levels through NR/NMN, and on the other hand, fisetin as a Senolytic clears aging cells and reduces SASP to inhibit the formation of M1 macrophages and the expression of CD38, thereby reducing cellular consumption of NAD+. Moreover, both compounds inhibit the formation of aging cells through multiple pathways, exerting a lasting anti-aging effect.
Not only does fisetin act at the cellular level to fundamentally slow down aging, but it also directly improves symptoms of age-related discomforts such as memory decline, osteoporosis, chronic inflammation, etc [37]. Fisetin can be considered as a foundational and comprehensive nutrient for achieving cellular anti-aging.
Through exploring scientific theories and finding ways to combat aging, we can better understand that aging is not only a complex and multifactorial biological process but also an important challenge for humans to understand the essence of life and enhance the quality of life. By gaining a deeper understanding of the mechanisms and influencing factors of cellular aging, we can more effectively explore methods to delay aging, bringing a brighter future for human health and happiness.
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