Members

Theme Leader :
Akihito Ishigami, Ph.D. Vice-director
Researcher :
Yasunori Fujita, Ph.D.

Keywords

Senescent cells, Age-associated genes, Single-cell analysis, Stress response, Secretory factors, Older adults, Mortality, Age-associated diseases

Major Research Titles

1. Identification of age-associated genes and senescent cells by single-cell analysis
2. Identification of senescent cells associated with stress-responsive secretory factors

Profile

1. Identification of age-associated genes and senescent cells by single-cell analysis
Recently, the presence of senescent cells, which are diminished functional capacity, in tissues of aged animals has been increasingly recognized. Identifying these cells and characterizing their properties are essential for understanding the complex mechanisms underlying aging. Our research group performs single-cell expression analysis (Nx1-seq: Next-generation 1-cell sequencing) to comprehensively explore and identify age-associated genes* at the single-cell level. Using the genes identified through this approach as markers, we aim to detect senescent cells present in tissues of aged animals and to elucidate the molecular mechanisms responsible for their functional decline.
*"Age-associated genes" include not only genes that are directly involved in aging mechanisms, but also genes whose expression changes during aging, even if they are not directly involved in the aging process.

2. Identification of senescent cells associated with stress-responsive secretory factors
Cells that constitute living organisms maintain their physiological functions while continuously adapting to various types of stress. However, persistent and excessive stresses lead to an accumulation of cells with reduced functional capacity, which in turn increases the risk of aging and age-related diseases. We have found that cells with impaired mitochondrial function secrete growth differentiation factor 15 (GDF15). GDF15 is a stress-responsive secretory factor whose circulating levels increase with age. Moreover, higher blood levels of GDF15 are associated with an increased risk of mortality and age-related diseases. These observations suggest that cells secreting GDF15 may represent senescent cells that accumulate during aging. We aim to identify senescent cells that exhibit high GDF15 expression in tissues of aged animals and to clarify their characteristics and the underlying mechanisms. Ultimately, we seek to establish strategies for regulating aging that may suppress the progression of aging and the onset of age-related diseases.

References

1. Oba K, Ishikawa J, Tamura Y, Fujita Y, Ito M, Iizuka A, Fujiwara Y, Kodera R, Toyoshima K, Chiba Y, Tanaka M, Araki A. Serum Growth Differentiation Factor 15 Levels Predict the Incidence of Frailty among Patients with Cardiometabolic Diseases. Gerontology 70:517-525, 2024.
2. Doshida Y, Hashimoto S, Iwabuchi S, Takino Y, Ishiwata T, Aigaki T, Ishigami A. Single-cell RNA sequencing to detect age-associated genes that identify senescent cells in the liver of aged mice. Sci Rep 13:14186, 2023.
3. Fujita Y, Shinkai S, Taniguchi Y, Miura Y, Tanaka M, Ohsawa I, Kitamura A, Ito M. Association Between Serum GDF15 Concentration and Total Mortality in Community-Dwelling Japanese Older Populations: The Involvement of Renal Dysfunction. J Gerontol A Biol Sci Med Sci 78: 1701-1707, 2023.
4. Fujita Y, Iketani M, Ito M, Ohsawa I. Temporal changes in mitochondrial function and reactive oxygen species generation during the development of replicative senescence in human fibroblasts. Exp Gerontol 165: 111866, 2022.
5. Oba K, Ishikawa J, Tamura Y, Fujita Y, Ito M, Iizuka A, Fujiwara Y, Kodera R, Toba A, Toyoshima K, Chiba Y, Mori S, Tanaka M, Ito H, Harada K, Araki A. Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease. Geriatr Gerontol Int 20: 980-987, 2020.
6. Fujita Y, Ito M, Ohsawa I. Mitochondrial stress and GDF15 in the pathophysiology of sepsis. Arch Biochem Biophys 696: 108668, 2020.
7. Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr Gerontol Int 16 Suppl 1:17-29, 2016.
8. Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, Kojima T, Ito M, Tanaka M, Saiki R, Koga Y. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol 78:814-23, 2015.
9. Fujita Y, Ito M, Kojima T, Yatsuga S, Koga Y, Tanaka M. GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion 20:34-42, 2015.