Unveiling the Characteristics of Mid-Old Cells: Insights into Aging and Rejuvenation

21 December 2023

Exploring the Markers and Functions of Mid-Old Cells in vitro and in vivo

Aging is an inevitable process that affects all living organisms, leading to a decline in physiological functions and an increased susceptibility to various diseases. While the mechanisms underlying aging are complex and multifaceted, recent research has focused on understanding the characteristics of mid-old cells, a critical stage in the aging process. By elucidating the markers and functions of mid-old cells, scientists hope to gain insights into the aging process and potentially develop strategies for rejuvenation. In this article, we delve into the latest research on mid-old cells, shedding light on their unique features and their implications for aging and rejuvenation.

Identifying Mid-Old Cells in vitro

Researchers embarked on a quest to identify mid-old cells in elderly tissue in vivo by studying their markers and characteristics in an in vitro culture model. Through sub-culturing primary human fibroblasts in increasing passages, they observed distinct changes in morphology, proliferation, and expression of senescence markers. Based on doubling time and SA-β-Gal positivity, the fibroblasts were categorized into three groups: young, mid-old, and old cells. Interestingly, mid-old cells exhibited a unique gene expression pattern, distinct from both young and old cells. They also showed a closer resemblance to young cells than to old cells in terms of gene expression patterns. Furthermore, mid-old cells displayed upregulation of genes related to peptide metabolism, suggesting an increased protein metabolism characteristic of mid-old cells.

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Functional Capacity of Mid-Old Cells

To investigate the functional changes in fibroblasts during the aging process, researchers conducted gene set enrichment analysis (GSEA) using hallmark gene sets. The analysis revealed a clear senescence phenotype only in old cells, while mid-old cells showed no significant differences in inflammatory response compared to young cells. However, the IL1β signaling pathway was specifically upregulated in mid-old cells, suggesting a distinct inflammatory response in this cell population. Additionally, mid-old cells exhibited a preserved capacity to respond to external stimuli, as demonstrated by the efficient translocation of Erk1/2 into the nucleus upon serum stimulation.

Presence of Mid-Old Cells in Elderly Tissues

To validate the presence of mid-old cells in elderly tissues, researchers performed immunohistochemistry (IHC) analysis on colon and lung tissues from elderly subjects. They observed marked upregulation of p21Waf1 in stromal cells of elderly tissues, along with increased expression of mid-old-specific inflammatory genes, IL1β and SAA1. These findings were consistent with the in vitro data, suggesting the presence of mid-old cells in elderly organs. Furthermore, the expression of SLIT2, an anti-inflammatory protein, was downregulated in elderly tissues, indicating a shift towards a chronically inflammatory state.

Functional Role of SAA1 in Elderly Tissues

SAA1, an acute response protein, was found to be highly upregulated in mid-old cells and elderly tissues. In vitro experiments demonstrated that SAA1 increased the expression of matrix metalloproteinases (MMPs) in fibroblasts and smooth muscle cells, potentially leading to the degradation of extracellular matrix (ECM) components. In elderly tissues, increased MMP9 expression and decreased type IV collagen levels were observed, suggesting ECM degradation. Additionally, SAA1 was found to induce muscle atrophy-related genes in smooth muscle cells. These findings suggest that SAA1 contributes to the development of aging-related microenvironments by promoting ECM degradation and muscle atrophy.

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Anti-Aging Effects of Young Cells and SLIT2

Researchers explored the potential of young cells to reverse the aging phenotype of mid-old cells. Co-culturing mid-old cells with young cells or treating them with conditioned media from young cells resulted in a significant increase in their proliferative capacity and functional recovery. RNA-sequencing analysis revealed the upregulation of various functional criteria in mid-old cells co-cultured with young cells. Further investigations identified SLIT2, a protein secreted by young cells, as a key factor in reversing the aging phenotype of mid-old cells. Treatment with recombinant human SLIT2 protein (rhSLIT2) restored the morphology and proliferative capacity of mid-old cells, accompanied by decreased levels of p21Waf1. Downregulation of SLIT2 in young cells led to increased expression of inflammatory genes and decreased proliferation, while adding back rhSLIT2 protein rescued the inflammatory gene expression. These findings highlight the crucial role of SLIT2 in reversing the aging phenotype of mid-old cells.

Anti-Aging Effects of SLIT2 in Aged Mice

To validate the anti-aging effects of SLIT2 in vivo, aged mice were treated with recombinant mouse SLIT2 protein (rmSLIT2). The treatment resulted in increased activity, inhibition of muscle mass reduction, and decreased expression of p21Waf1 in stromal-rich organs. Additionally, the number of SOX2-expressing cells, known as stem cell factors, increased in rmSLIT2-treated mice. These findings demonstrate the potential of SLIT2 as an anti-aging molecule in aged mice.

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The study of mid-old cells has provided valuable insights into the aging process and potential strategies for rejuvenation. By identifying the markers and characteristics of mid-old cells, researchers have shed light on the unique features of this critical stage in the aging process. The presence of mid-old cells in elderly tissues and their distinct gene expression patterns suggest their role in the aging phenotype. Furthermore, the anti-aging effects of young cells and the key role of SLIT2 in reversing the aging phenotype of mid-old cells offer promising avenues for further research and potential therapeutic interventions. As scientists continue to unravel the complexities of aging, these findings bring us one step closer to understanding and potentially controlling the aging process.

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