Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing

Abstract

Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells 1,2 . It has been proposed that this is at least partially caused by the senescence of progenitors with age 3,4 ; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16 INK4a , which encodes a cyclin-dependent kinase inhibitor linked to senescence 5 . Ageing p16 INK4a -deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16 INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16 INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16 INK4a expression.Stem cells must persist throughout adult life in numerous tissues, including the central nervous system (CNS) 6 , in order to replace the mature cells that are lost to turnover, injury, or disease. However, the function of stem cells and other progenitors declines with age in diverse tissues including the haematopoietic system 7-9 , muscle 10,11 and brain 6,12,13 . Consistent with this, ageing tissues exhibit reduced repair capacity and an increased incidence of degenerative disease 1,4 . However, the mechanisms responsible for the age-related decline in the function of stem cells and other progenitors remain uncertain.

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…The senescence biomarker p16 INK4a mediates cell cycle arrest through inhibition of cyclin‐dependent kinase 4 and 6 (CDK4/6), but p16 INK4a expression is not required for production of the SASP (Coppe et al., 2011). Furthermore, in vivo evidence suggests that the primary functional consequence of high p16 INK4a expression with aging is to limit the proliferation of specific cell types during homeostasis or in response to injury (Janzen et al., 2006; Krishnamurthy et al., 2006; Liu et al., 2011; Molofsky et al., 2006; Sousa‐Victor et al., 2014). Several groups, however, have suggested cell cycle independent effects of p16 INK4a and CDK4/6 inhibition (Goel et al., 2017; Murakami, Mizoguchi, Saito, Miyasaka & Kohsaka, 2012), and it is unclear whether reduced p16 INK4a expression can protect tissues from age‐related pathologies that are associated with the SASP but not with replicative failure.…”

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

“…Aging is associated with reduced neurogenesis in the mouse SVZ and SGZ (Encinas et al., 2011; Enwere et al., 2004; Lugert et al., 2010; Luo, Daniels, Lennington, Notti & Conover, 2006), which might lead to decreased olfactory function and cognitive hippocampus‐dependent impairment (Goncalves et al., 2016; Lledo & Valley, 2016). This age‐associated neurogenic decline appears to be caused both by a depletion in the NSPC pool of the aged niche (Ahlenius, Visan, Kokaia, Lindvall & Kokaia, 2009; Bouab, Paliouras, Aumont, Forest‐Berard & Fernandes, 2011; Corenblum et al., 2016; Enwere et al., 2004; Luo et al., 2006; Maslov, Barone, Plunkett & Pruitt, 2004; Molofsky et al., 2006; Stoll et al., 2011) and by the decreased capacity of the remaining NSPCs to sustain proliferation and neuronal differentiation, as revealed by in vitro studies (Ahlenius et al., 2009; Apostolopoulou et al., 2017; Corenblum et al., 2016; Daynac, Morizur, Chicheportiche, Mouthon & Boussin, 2016; Daynac et al., 2014; L'Episcopo et al., 2013; Shi et al., 2017; Zhu et al., 2014). NSPCs undergo cell autonomous age‐related changes that affect intracellular molecular pathways, including the altered expression of telomerase and cell cycle regulators, which have been linked to the decline in NSPC proliferation upon aging (Caporaso, Lim, Alvarez‐Buylla & Chao, 2003; Molofsky et al., 2006; Nishino, Kim, Chada & Morrison, 2008).…”

“…This age‐associated neurogenic decline appears to be caused both by a depletion in the NSPC pool of the aged niche (Ahlenius, Visan, Kokaia, Lindvall & Kokaia, 2009; Bouab, Paliouras, Aumont, Forest‐Berard & Fernandes, 2011; Corenblum et al., 2016; Enwere et al., 2004; Luo et al., 2006; Maslov, Barone, Plunkett & Pruitt, 2004; Molofsky et al., 2006; Stoll et al., 2011) and by the decreased capacity of the remaining NSPCs to sustain proliferation and neuronal differentiation, as revealed by in vitro studies (Ahlenius et al., 2009; Apostolopoulou et al., 2017; Corenblum et al., 2016; Daynac, Morizur, Chicheportiche, Mouthon & Boussin, 2016; Daynac et al., 2014; L'Episcopo et al., 2013; Shi et al., 2017; Zhu et al., 2014). NSPCs undergo cell autonomous age‐related changes that affect intracellular molecular pathways, including the altered expression of telomerase and cell cycle regulators, which have been linked to the decline in NSPC proliferation upon aging (Caporaso, Lim, Alvarez‐Buylla & Chao, 2003; Molofsky et al., 2006; Nishino, Kim, Chada & Morrison, 2008). Transcriptional analysis of the aged whole SVZ cell population (including NSPCs, differentiated cells and non‐neural cell types) identified several misregulated genes that are associated with NSPC proliferation and differentiation, suggesting that intrinsic gene expression changes in aged NSPCs can alter adult neurogenesis (Apostolopoulou et al., 2017; Shi et al., 2017).…”

Relationships between stem cell exhaustion, tumour suppression and ageing

“…For some tissues, this expectation has been fulfilled, at least in part. Age-related decline in proliferation of the forebrain progenitors, pancreatic b-islet cells and HSCs were rescued significantly upon deletion of p16 INK4A in mice, as were regeneration of the corresponding tissues (Janzen et al, 2006;Krishnamurthy et al, 2006;Molofsky et al, 2006). These studies strongly indicate that naturally occurring upregulation of p16 INK4A levels with age form a ratelimiting block in tissue regeneration and that deletion of p16 INK4A alone is sufficient to remove at least part of this blockade.…”