Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo

Omori, Satotaka; Wang, Teh Wei; Johmura, Yoshikazu; Kanai, Tomomi; Nakano, Yasuhiro; Kido, Taketomo; Susaki, Etsuo A.; Nakajima, T.; Shichino, Shigeyuki; Ueha, Satoshi; Ozawa, Manabu; Yokote, Kisho; Kumamoto, Soichiro; Nishiyama, Atsuya; Sakamoto, Takeharu; Yamaguchi, Kiyoshi; Hatakeyama, Seira; Shimizu, Eigo; Katayama, Kotoe; Yamada, Yasuhiro; Yamazaki, Satoshi; Iwasaki, Kanako; Miyoshi, Chika; Funato, Hiromasa; Yanagisawa, Masashi; Ueno, Hikaru; Imoto, Seiya; Furukawa, Yoichi; Yoshida, Nobuaki; Matsushima, Kouji; Ueda, Hiroki R.; Miyajima, Atsushi; Nakanishi, Makoto

doi:10.1016/j.cmet.2020.09.006

Cited by 119 publications

(99 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We provide a potential mechanistic pathway by which senescence can lead to steatosis, through inhibition of CDK1 activity, eventually leading to FFA-induced chronic hyperinsulinemia and the consequent insulin resistance. More recently, Omori et al(113) uncovered that senescence is also increased in the hepatic non-parenchymal cell population. Furthermore, they confirmed that elimination of senescent cells rescues the NASH phenotype.…”

mentioning

confidence: 99%

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Cadez

Zafer

et al. 2020

eLife

View full text Add to dashboard Cite

Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.

show abstract

mentioning

confidence: 99%

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Cadez

Zafer

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…Relative to the youthful state, quiescent and senescent cells exhibit upregulation of various secreted factors (92), as well as elevated metabolic activities (93), rather than global downregulation of cellular activities. Moreover, similar to the macroscopic appearance of hair graying, age-related senescence naturally occurs among cells heterogeneously scattered within tissues (94), beginning as early as a few weeks after birth in mice (95), and the age-related accumulation of senescenceassociated DNA methylation changes among cell populations also exhibit stochasticity (96). Our data reveal that the conserved principle of an age-related increase in molecular and cellular heterogeneity is reflected not only at the tissue level (mixture of dark and white hairs) but also in the graying hair proteome.…”

Section: Discussionmentioning

confidence: 94%

“…Hair graying is a ubiquitous, visible, and early feature of human biological aging 1 . In aging mammalian tissues, senescent cells appear stochastically beginning early in life 2, 3 .…”

mentioning

confidence: 99%

“…Hair graying is a ubiquitous, visible, and early feature of human biological aging 1 . In aging mammalian tissues, senescent cells appear stochastically beginning early in life 2,3 . Similarly, individual hair follicles (HFs) on the scalp and other body regions undergo depigmentation in a stochastic, age-related manner 4 .…”

mentioning

confidence: 99%

“…Phenotypically, the age-related instability and depigmentation of the HF therefore parallels the increased episodic molecular instability 5 and cell-to-cell heterogeneity that characterizes biological aging 6–8 . In mice, cells expressing canonical senescent signatures (e.g., P16 INK4a ) begin to appear in multiple organs as early as a few weeks after birth 3,9 , documenting age-related cellular transitions appearing early in life. Sensitive detection methods in tissues with unambiguous age-related phenotypes, such as hair shaft depigmentation or graying, could similarly reveal early age-related phenotypes and their modifiability in humans.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

Rosenberg

Rausser

Ren

et al. 2020

Preprint

View full text Add to dashboard Cite

Hair graying is a universal hallmark of aging 1 but its mechanisms are insufficiently understood 2 and its reversibility in humans remains uncertain. Moreover, while psychological stress accelerates human biological aging 3,4 and triggers hair graying in animals 5 , no prior study has longitudinally examined the stress-to-hair graying connection in humans. Here we develop an approach to quantitatively profile natural graying events and their associated proteomic signatures along individual human hairs, resulting in a quantifiable physical timescale of aging.Using this approach, we identify white hairs that naturally regain pigmentation within days to weeks in healthy young individuals across sex, ethnicities, ages, and body regions, demonstrating that human hair graying is naturally reversible. Proteomic analysis of matched dark and white hairs replicated across two independent experiments show that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Coordinated graying and reversal also occur simultaneously across multiple scalp hair follicles of a person, suggesting that unknown systemic factors influence hair graying patterns. Combining hair pigmentation profiling and proteomics at the single hair shaft level, we also report hair graying and reversal occurring in parallel with behavioral and psychological stressors. A computational simulation of life-long and stress-induced hair graying suggests a threshold-based mechanism for the rapid reversibility of graying. Together, these findings document the reversibility of hair graying in humans and provide a new model to examine the modifiability of human aging.

show abstract

Detecting cellular senescence in vivo: Imagining imaging better

Rabinowitz

Cui

2023

Aging and Cancer

View full text Add to dashboard Cite

Methods to detect cellular senescence have become increasingly important, even more so in living animals and humans. This cellular state has been found to play fundamental roles in physiological processes as well as functioning detrimentally toward the advent or progression of pathological conditions. Importantly, the study of senescence involvement in these processes in vivo cannot be done without living‐friendly technologies enabling senescence detection. Furthermore, senotherapies or therapies that selectively kill senescent cells have emerged as a new therapeutic strategy for aging and age‐related diseases such as atherosclerosis, cancer, and neurodegenerative disorders and require tools to evaluate their use in vivo. As of now, our in vivo senescence detection toolkit includes genetically engineered reporter mouse models and small molecule imaging probes. Herein, we will focus on the detection of senescence in vivo, including a summary of its challenges, current detection methods and strategies, and a perspective on overcoming the current obstacles.

show abstract

Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo

Cited by 119 publications

References 97 publications

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

Detecting cellular senescence in vivo: Imagining imaging better

Contact Info

Product

Resources

About