Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Baker DJ et al. (2016) Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan. //////////////////INK4 family of cyclin-dependent kinase inhibitors are important in cell division and tumorigenesis.
Aged cells have higher levels of Ink4/Arf, which limits the efficiency and fidelity of reprogramming.,,,,,,,,,,,Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
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identified T2D susceptibility loci in or near CDKAL1, CDKN2A and CDKN2B,
NCBI Summary:
This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
Ink4a/Arf expression is a biomarker of aging.
Krishnamurthy J, et al .
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16(INK4a) and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16(INK4a) and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16(INK4a) and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16(INK4a) transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.
Expression regulated by
Comment
Ovarian localization
Granulosa
Comment
Arcellana-Panlilio MY, et al reported the evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors
Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for
<5% of all ovarian cancers. The molecular pathogenesis of these tumors is not
well understood. The authors tested the hypothesis that cycl in-dependent kinase
inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4
(INK4) family, are targets for altered gene expression in GCTs. The status of
RBI, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian
GCTs was determined by reverse transcription-polymerase chain reaction of
total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of
INK4A expression were assayed further by exon-deletion analysis and
methylation-specific PCR. None of the juvenile tumors demonstrated altered
expression, but 7/12 (S8%) adult GCTs lacked expression of INK4A, INK4B, or
both. In one of these cases, the authors noted a homozygous deletion of the INK4A
locus, and in the remaining tumors hypermethylation of the promoter
region, a mechanism that can lead to gene inactivation. These data support a
role for the INK4 family of CDK inhibitors in the biology of GCTs.
Follicle stages
Antral
Comment
Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion. Ansere VA et al. (2021) Decline in ovarian reserve with advancing age is associated with reduced fertility and the emergence of metabolic disturbances, osteoporosis, and neurodegeneration. Recent studies have provided insight into connections between ovarian insufficiency and systemic aging, although the basic mechanisms that promote ovarian reserve depletion remain unknown. Here, we sought to determine if chronological age is linked to changes in ovarian cellular senescence, transcriptomic, and epigenetic mechanisms in a mouse model. Histological assessments and transcriptional analyses revealed the accumulation of lipofuscin aggresomes and senescence-related transcripts (Cdkn1a, Cdkn2a, Pai-1 and Hmgb1) significantly increased with advancing age. Transcriptomic profiling and pathway analyses following RNA sequencing, revealed an upregulation of genes related to pro-inflammatory stress and cell-cycle inhibition, whereas genes involved in cell-cycle progression were downregulated; which could be indicative of senescent cell accumulation. The emergence of these senescence-related markers preceded the dramatic decline in primordial follicle reserve observed. Whole Genome Oxidative Bisulfite Sequencing (WGoxBS) found no genome-wide or genomic context-specific DNA methylation and hydroxymethylation changes with advancing age. These findings suggest that cellular senescence may contribute to ovarian aging, and thus, declines in ovarian follicular reserve. Cell-type-specific analyses across the reproductive lifespan are needed to fully elucidate the mechanisms that promote ovarian insufficiency.//////////////////