Aging is a major risk factor for various types of functional loss as well as highly prevalent chronic or fatal diseases (Niccoli and Partridge, 2012; Crimmins, 2015). During aging, the human brain displays a decrease in gray and white matter and an enlargement of the ventricles, with the development of abnormal protein assemblies that trigger cognitive impairment or further deterioration into neurodegenerative disease (Scheltens et al., 2016; Aarsland et al., 2017). Therefore, exploring the molecular mechanisms underlying the normal brain aging process may provide new ideas and strategies for the treatment of neurodegenerative diseases as well as other diseases caused by aging.

Neural progenitor cells (NPCs) exist in a resting state that is activated by stimuli from the internal or external brain environment (Vadodaria and Gage, 2014) and eventually differentiate into mature neurons and glial cells (Ma et al., 2009) during neurogenesis. Neurogenesis is a neuroprotective mechanism by which newborn neurons can retain the potential to develop into fully mature and functional granule cells despite changes in the local microenvironment of the brain during aging (Lazarov et al., 2010). The DG (dentate gyrus) region of the hippocampus and the SVZ (subventricular zone) are the two main areas of the brain that produce NPCs (Vadodaria and Gage, 2014). Neurogenesis in the rat brain has been shown to decrease in adulthood but some activity still remains in older age (Kuhn et al., 1996). Abnormal oxidative stress, impaired DNA repair, and inflammation in aging NPCs may lead to a reduction in age-related neurogenesis (Ekdahl et al., 2003; L'Episcopo et al., 2013). The proliferation of NPCs gradually decreases with aging until 12 months old, stabilizing afterwards at a lower level (Stoll et al., 2011).

NPCs differentiate into glial cells that promote neuronal migration and development, which is pivotal for balancing the immune environment within the central nervous system (CNS) (Siebzehnrubl et al., 2011). Astrocytes, the most abundant glial cells in the brain, are essential for maintaining the normal functions of the CNS by participating in the formation of neuronal synapses (Allen et al., 2012) and mediating the uptake and recycling of neurotransmitters (Rothstein et al., 1996). Astrocytes have been shown to possess altered activation morphology in the hippocampus during human aging (Allen et al., 2012). Furthermore, a large number of reactive hippocampal and striatal astrocytes have been observed during the aging process (Clarke et al., 2018).

The overall functional decline of living organisms over time is known as senescence (Lopez-Otin et al., 2013). The main reason for cellular senescence is cell cycle arrest caused by increased expression levels of cyclin-dependent kinase inhibitors (CDKIs) such as p16 (INK4a, an inhibitor of CDK4), p15 (CDKN2B), p53, p21 (Cip1/Waf1), and p19 (Arf) (Matheu et al., 2007; Capparelli et al., 2012). Among them, p53 is a key regulator of the cell cycle, increased phosphorylation of which leads to cell cycle arrest. p21 is a downstream CDKI of phosphorylated p53 and blocks cell cycle entry into G1/S phase following CDK2 binding (LaPak and Burd, 2014). In addition, cellular senescence is accompanied by an inflammatory response, during which the expression of pro-inflammatory factors, including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), are elevated (Munoz-Espin and Serrano, 2014). Notably, neuroinflammation accelerates the development of age-related diseases of the CNS (Hong et al., 2016). Protein kinase B (PKB), also known as Akt, is a proto-oncogene that plays a major role in the regulation of cell growth, proliferation, and transcription (Revathidevi and Munirajan, 2019). Phosphorylation of Akt further affects the activation status of various downstream effectors, including p53 and the transcription factor family FOXO (Bai et al., 2017; Chen et al., 2020), which are vital for the maintenance of cellular homeostasis (Martins et al., 2016). Following the activation of upstream Akt kinases, Foxo3a is further phosphorylated and loses functional regulatory capacity due to translocation from the nucleus to the cytoplasm (Lu et al., 2016).

Dcf1, also known as transmembrane protein 59 (TMEM59), is abundantly expressed in dendritic cells and plays an essential role in their maturation (Wang et al., 2019). Dcf1 is vital to the nervous system; its deletion leads to a reduction in a variety of neuronal dendrites, and its overexpression can rescue the structure and function of neuronal dendrites (Li et al., 2021). Our previous studies have shown that Dcf1 regulates social behaviors including social cognition, learning, and memory (Wang et al., 2019). Moreover, we also found that silencing Dcf1 in NSCs promotes their differentiation, and overexpression of Dcf1 maintains the stem cell properties of NSCs (Wang et al., 2008). Furthermore, we previously demonstrated that overexpression of Dcf1 in the Drosophila PD model prolongs lifespan by 23 %, leading to α-synuclein degradation in vitro and in vivo (Zhang et al., 2018). Taken together, these data strongly suggest that Dcf1 mediates aging.

Here, we explored the mechanism underlying the effect of Dcf1 on aging. Using Dcf1−/− mice, we show that Dcf1 delays aging from the aspect of brain neurogenesis, cellular aging, molecular signaling, and learning and memory behavior, providing a deeper understanding of the aging process and the maintenance of brain vitality.