When cells are exposed to stress and damage, cellular senescence occurs. This phenomenon increases with aging.
Senescent cells (SnCs) achieve a permanent growth arrest and exhibit a senescence-associated secretory phenotype (SASP). Although several studies have indicated that SASP is associated with age-related pathologies and phenotypes in a paracrine manner, the physiological role of SnCs in aged mammals is not well understood.
Study: Systemic induction of senescence in young mice after a single heterochronic blood exchange. Image credit: Anusorn Nakdee / Shutterstock.com
background
Heterochronic parabiosis is a surgical technique that offers a parabiotic mating of two animals of different ages. This process rejuvenates old tissues and ages young tissues.
Heterochronic parabiosis involves the surgical joining of young and old mice sharing blood and organs, as well as their environments.
Previously, heterochronic parabiosis using old plasma dilution and blood exchange revealed that age-related factors are systematically propagated and have progeronic effects in young mice. However, the mechanistic role of blood-borne factors in promoting aging remains unclear.
About the study
In a recent study in Nature Metabolism, scientists performed a heterochronic blood exchange in male mice and observed that aged mouse blood triggered cell and tissue senescence in younger mice.
We evaluated different tissues after blood heterochronicity experiments to understand the role of cellular senescence in promoting physiological aging phenotypes. The effect of SnCs, which is triggered during normal aging, and their circulation in old mice was also determined. In addition, we assessed the systematic induction of senescence and aging in young mice.
Results of the study
Cellular senescence occurs in response to extrinsic and intrinsic signals. Some of the factors that trigger senescence include genomic damage, metabolic imbalances, mitochondrial dysfunction, and mitogenic signals induced by activated oncogenes.
SnCs, partially through the senescence-associated secretory phenotype (SASP), induce secondary senescence. Secondary senescence is involved with the senescence response in nearby non-senescent cells. Based on this observation, scientists postulated the possibility of transferring senescence from old animals to young animals without chronological aging.
In vivo and in vitro experiments were performed to determine the role of SnCs using mouse and human plasma and blood transfer from old to young mice.
To understand the pro-aging effects of aging systemic environments, non-senescent cells from humans and mice were cultured in the presence of serum from young or old mice, or plasma from young or old individuals. In this experiment, the serum of four-month-old mice was compared with that of thirty-two-month-old mice.
This comparison revealed that serum from old mice showed enhanced expressions of senescence-regulated genes Cdkn2a and Cdkn1a, as well as SASP factors such as Il6 and Mmp3 compared to younger mice. This finding was determined using a cytokine array.
Older mice also showed reduced expression of the senescence-regulated gene Lmnb1 than younger mice, while senescence-associated β-galactosidase (SA-β-gal) was upregulated.
Reduction of cell proliferation in old mice was measured by incorporation of 5-ethynyl-2′-deoxyuridine (EdU). A significant decrease in high mobility group box1 (HMGB1) and laminB1 was observed.
One group of mice was treated with serum from old mice, while the other was treated with a mixture of serum from old and young mice. This experiment revealed the dominance of serum from aged mice, strongly suggesting that senescent phenotypes of aged mice can be transferred to non-senescent mouse dermal fibroblasts (MDF) via serum.
Heterochronic blood exchanges were performed between young and old mice, with a control setting using isochronic exchanges. Bioluminescence of the p16-3MR reporter was monitored to assess whether old blood could systematically induce senescence in young p16-3MR mice.
After 14 days of blood exchange, a significant elevation of whole-body bioluminescence was observed in young p16-3MR mice that received blood from old mice. This observation was not made in the control group.
A premature aging phenotype was observed when SnCs induced by irradiation in culture were transplanted into young mice. This observation is similar to previous studies reporting that transplantation of irradiated cells into young mice resulted in reduced muscle and physical strength compared with transplants of non-irradiated cells.
After seven days of transferring old blood to young mice, the young mice performed poorly on the four-limb hanging test; however, performance improved after fourteen days. No significant structural or functional changes were observed in young kidneys after exposure to old blood.
The scientists suggested that senolytics could be used to prevent the systemic spread of senescence. This could also be used to better understand aging and develop rational therapies to extend life.
Conclusions
The naturally occurring SnCs of old age appear to play an important role in promoting the systemic spread of aging, particularly in the kidney, liver, and muscle.
Both in vivo and in vitro experiments with mice and humans demonstrate the possibility of senescence transfer using SnCs. Thus, SnCs could be aimed at generating new therapeutic strategies.
Journal reference:
- Jeon, OH, Mehdipour, M., Gil, T., et al. (2022) Systemic induction of senescence in young mice after a single heterochronic blood exchange. Metabolism of nature. doi:10.1038/s42255-022-00609-6