#Skin cell turnover rate by age series#

In normal cells the mitochondria undergo dynamic changes in morphology regulated in part by the fission factor Drp1( Otera et al., 2013).

The anti-apoptotic “Bcl-2 family” proteins(e.g., Bcl-2, Bcl-x and Bcl-xL) can bind to the pro-apoptotic proteins to inhibit pore formation. The pro-apoptotic “Bcl-2 family” proteins include several of the “BH3-only” class (e.g., Bid, Bim, Puma)that promote permeabilization of the mitochondria by activating “Bcl-2 family” members Bad and Bax to form a pore structure in the mitochondrial membrane( Westphal et al., 2014). Cells contain a mix of pro-apoptotic and anti-apoptotic “Bcl-2 family” proteins and are poised for entry into the apoptotic pathway if and when the balance is sufficiently altered. The mitochondria play a central role in regulating the apoptotic pathway and caspase activation in mammalian cells. Initiator caspases (e.g., caspase-9) cleave and activate downstream effector caspases (e.g., caspase-3), which in turn cleave numerous cellular proteins including those of the cytoskeleton. Under appropriate conditions the caspases can activate themselves through autocatalytic cleavage, and can also cleave and activate other caspases, thereby creating a self-amplifying cascade. The caspases are present in the cytoplasm of most cells, mostly in an inactive form (procaspase).

#Skin cell turnover rate by age series#

The molecular mechanism of apoptosis includes the sequential activation of a series of cysteine proteases called the caspases ( Figure 1)( Shalini et al., 2015). Because no cellular material is released into the interstitial space, and the engulfing cells do not release inflammatory cytokines, there is no immune reaction to apoptosis. The small size of the apoptotic bodies facilitates their engulfment by nearby macrophages and other cells through phagocytosis, where the materials are further broken down in phagolysosomes for recycling. This is followed by a fragmentation of the nucleus and chromatin called karyorrhexis, cell membrane blebbing, and finally the budding of the cell into a series of membrane-bound structures called apoptotic bodies. The first visible changes of apoptosis are the shrinkage of the cell, and a condensation of the nucleus and chromatin called pyknosis. The exposed phosphatidylserine ultimately serves as a signal to nearby macrophages to engulf the dying cell. One of the earliest molecular markers of apoptosis is the externalization of cell membrane phosphatidylserine, which can be detected by staining with the reagent Annexin V( Hankins et al., 2015 Leventis and Grinstein, 2010). The canonical form of PCD is apoptosis( Elmore, 2007 Kerr et al., 1972), sometimes called type I PCD, in which the cell undergoes a characteristic series of molecular, biochemical and morphological changes.

However, more recently it has become clear that the PCD and necrosis mechanisms can sometimes overlap, and that necrosis is a more regulated process than was previously assumed( Galluzzi et al., 2012). In addition, necrotic cell death typically causes a strong immune response, whereas PCD does not ( Proskuryakov and Gabai, 2010 Taylor et al., 2008).

PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.Ĭell death mechanisms have traditionally been divided into two types, programmed cell death (PCD) mechanisms that require energy, and necrotic cell death mechanisms that do not( Elmore, 2007). PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. During aging the cell turnover rate declines for several highly-mitotic tissues.

Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis.