Aging is a common biological phenomenon that involves the decline of cell, tissue, organ, and organism function. It is a major risk factor for a variety of chronic diseases. Wrinkled skin, the gradual accumulation of age-related pigments, limited mobility, disrupted hormone secretion, poor memory function, and degenerative changes in various tissues and organs are all symptoms of the human aging process. The aging process, from the onset to the emergence of degenerative changes, often takes several decades and is influenced by a combination of programmed biological regulations and other factors.

Aging has an impact not only on people's health and longevity, but it also has a big impact on society and the economy. Exploring the mechanisms and interventions of aging has thus long been an important topic in life sciences and medical research. The aging population problem is growing more relevant as society and the economy evolve, and aging research is garnering increased attention.

Scientific research on aging dates back to the 1930s, when it was discovered that limiting calorie intake in mice and rats might increase their lifespan. This study demonstrated the plasticity of the aging process and established the groundwork for further genetic investigations. Over the last few decades, hundreds of genes that can regulate longevity have been discovered by using model organisms such as yeast, nematodes, fruit flies, and mice for genetic screening and gene editing. This has revealed some critical signaling pathways and molecular processes.

Currently, the only mammalian model for rapid aging research is the senescence-accelerated mouse (SAM). The senescence-accelerated mouse/prone (SAMP) model shows age-related acceleration in the decay of learning and memory as well as pathological changes in the central nervous system, particularly the cortex and hippocampus. P1, P2, P3, P6, P7, P8, P9, P10, and P11 are some of the lines in the SAMP strain. SAMP models have been used to explore the mechanisms of aging and age-related decay of learning and memory, as well as to test anti-aging and cognitive-enhancing medicines. In addition to the SAMP model, there are naturally aging mice, Lmna mutant mice are used to simulate Hutchinson-Gilford progeria syndrome (HGPS) patients (with a lifespan of about 3 months), Sirt6 KO mice, and Klotho KO mice. Establishing models of aging in non-human primates is even more challenging than in mice.

Figure 1. Timeline of research on aging and aging-related diseases^[1]

Several signaling pathways have been identified as key modulators of aging and longevity, such as SIRT1, AMPK, mTOR, NF-κB, p53, PGC1α and FOXOs. These pathways interact with each other and respond to various environmental and metabolic stimuli, such as oxidative stress, inflammation, nutrient availability, and DNA damage. By modulating the expression and activity of genes involved in cellular processes such as metabolism, autophagy, senescence, apoptosis, and stem cell maintenance, these pathways influence the rate of aging and the onset of age-related diseases. Understanding the molecular mechanisms and interactions of these aging-related signaling pathways may provide novel insights and therapeutic strategies for promoting healthy aging and preventing or delaying age-related diseases.

Carlos López-Otín et al. summarized 12 common features of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis^[2]. Research on these aging features and related pathways is of great significance for the development of anti-aging drugs. For example, metformin, which can regulate mitochondrial function, exerts its anti-aging effects by inhibiting mitochondrial respiratory complex I, reactive oxygen species (ROS), and pro-inflammatory cytokines.

Figure 2. Hallmarks of aging: An expanding universe^[2]

Identification and characterization of aging-related genes can provide vital insights into the molecular mechanisms underlying the aging process as well as prospective targets for therapies targeted at delaying or preventing age-related decline and diseases. As a result, scientists are always looking for new aging-related genes that could be promising targets, such as SIRT1, mTOR, IGF-1, FOXO3, NRF2, p53, and ATM.

Recent research suggests that the TGF-β signaling pathway and its associated protein may play a crucial role in promoting healthy longevity. Specifically, SMAD7 serves to inhibit the TGF-β signaling pathway, while ACVR1 stimulates SMAD7, and TAB2 activates TAK1, which is released from the receptor complex and transmits TGF-β signaling downstream upon stimulation by TGF-β^[3]. Another study has shown that knocking out PARP1 can enhance mitochondrial biosynthesis and activity, increase resistance to starvation and oxidative stress, improve climbing ability, and significantly extend the lifespan of fruit flies, with AMPKα being an indispensable factor in this process^[4].

Aging research is a complex and promising field that spans various disciplines and levels, demanding collaboration and innovation from a variety of sources. We have reasons to expect that, with the advancement of science, technology and societal demand, we will realize the objective of healthy aging in the near future, thereby boosting the quality of life and well-being.

GemPharmatech has developed relevant mouse models as part of the Knockout All Project (KOAP) to enhance aging-related research. We anticipate that access to these high-quality models will expand researchers' access to animal models and significantly shorten the research cycle. Visit our website today to learn more.

Reference:

1. Guo, J., Huang, X., Dou, L. et al. (2022) Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduction and Targeted Therapy, 7, 391.

2. López-Otín, C., Blasco, M.A., Partridge, L. et al. (2022) Hallmarks of aging: An expanding universe. Cell. Available at: https://doi.org/10.1016/j.cell.2022.11.005 (Accessed: 8 June 2023)

3. Komaki, S., Nagata, M., Arai, E. et al. (2023) Epigenetic profile of Japanese supercentenarians: a cross-sectional study. The Lancet Healthy Longevity, 4(2), e83-e90.

4. Guo, S., Zhang, S., Zhuang, Y. et al. (2023) Muscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 120(13), e2213857120.