Loss of pregnancy‐associated plasma protein A extends lifespan in mice

Abstract

SummaryGenetic deletion in mice of pregnancy-associated plasma protein A (PAPP-A), a recently identified metalloproteinase in the insulin-like growth factor system, extends by 30-40% both mean and maximum lifespan with no reduction in food intake or secondary endocrine abnormalities. Furthermore, these mice have markedly reduced incidence of spontaneous tumors. The findings implicate PAPP-A as a critical regulator of lifespan and age-related diseases, and suggest PAPP-A as a possible target to promote longevity. Key words: gene knock-out; insulin-like growth factor I; longevity; mouse model; pregnancy-associated plasma protein A, tumors.The antagonistic pleiotropic theory of aging posits that genes can have opposite effects on biological fitness at different ages such that their effects are beneficial early in life but are detrimental to the organism later in life (Williams, 1957). This theory is relevant to the apparent paradox of the insulin-like growth factor (IGF) system. IGFs are essential for normal fetal development and are important stimulators of cell proliferation and survival (D'Ercole, 1996). However, IGFs are also associated with cellular and chronological aging, and with the increased incidence of vascular disease and cancer that occurs with age (D'Ercole, 1996;Bayes-Genis et al ., 2000;Pollak et al ., 2004;Katic & Kahn, 2005). Thus, it has been shown that a reduction in IGF-I signaling achieved by mutations in receptors or intracellular receptor substrates is associated with an increase in lifespan and delayed onset of age-related disorders in diverse species (Kenyon, 2001;Tatar et al ., 2003;Rincon et al ., 2004;Katic & Kahn, 2005). However, a specific connection between IGF and longevity in mammals has been difficult to demonstrate. The well-characterized Ames dwarf, Snell dwarf, lit/lit and growth hormone (GH) receptor knock-out mice have primary GHdeficiency or a GH signaling defect that has a secondary effect to decrease circulating levels of IGF-I (Brown-Borg et al ., 1996;Coschigano et al ., 2000;Flurkey et al ., 2001;Carter et al ., 2002). Circulating IGF-I is produced largely by the liver under predominant GH control, but IGF-I secretion also occurs in many tissues independent of GH. Low circulating IGF-I levels as a result of caloric restriction are also associated with increased lifespan in rodents (Sohal & Weindruch, 1996;Longo & Finch, 2003;Richardson et al ., 2004). Therefore, it is unclear whether IGF-I exerts its biological effects through endocrine or paracrine/autocrine mechanisms. Here, we present a novel model of local IGF-I suppression that dramatically extends lifespan in mice on an unrestricted diet and sharply reduces incidence of spontaneous tumors.The IGF system is complex with ubiquitous ligands and with receptors present on virtually all cells. In recent years, it has become increasingly clear that IGF binding proteins (IGFBP) and IGFBP proteinases are the ultimate determinants of IGF ligand availability and, hence, response (Bunn & Fowlkes, 2003). Pregnancy-associated ...

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…A number of "aging genes" have been identified for which mutations significantly increase mouse lifespan and delay the onset of age-related disease (Prop1, Pit1, Ghr,Ghrhr,Irs1,Irs2,PappA,Clk1,Shc1,Igf1r,Kl,Adcy5,Surf1,Insr,Ucp2,Gpx4) (Brown-Borg et al, 1996;Kopchick and Laron, 1999;Migliaccio et al, 1999;Flurkey et al, 2001;Bluher et al, 2003;Holzenberger et al, 2003;Kurosu et al, 2005;Liu et al, 2005;Conti et al, 2006;Conover and Bale, 2007;Dell'Agnello et al, 2007;Ran et al, 2007;Taguchi et al, 2007;Yan et al, 2007;Selman et al, 2008). The extent to which these genes interact with CR-regulated pathways is unclear (Miller et al, 2002;Tsuchiya et al, 2004;Bonkowski et al, 2006;Swindell, 2007).…”

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

“…Interestingly, neither mTORC1 nor mTORC2 was altered in mice with liver‐specific deletion of GHR, mice in which lifespan is normal despite dramatically lower levels of serum IGF‐1 (Bartke, 2008; Dominick et al ., 2015). The metalloproteinase PAPP‐A is thought to act by regulating local IGF‐1 action through degradation of some IGF‐1 binding proteins, particularly IGF‐BP4 (Conover & Bale, 2007). PAPP‐A deletion can extend both mean and maximum lifespan by 20–40%, with a reduced incidence of spontaneous tumors, without modulation of serum levels of GH or IGF‐1.…”

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

“…These remarkably long‐lived animals are characterized by reduced postnatal growth rate, delayed development, and reduced adult body size (Junnila et al ., 2013). Mice lacking Ghrh, or Ghrhr (Flurkey et al ., 2001; Sun et al ., 2013), are also long‐lived, as are mice lacking PAPP‐A, a protease specific for IGF‐1‐binding proteins (Conover & Bale, 2007), further implicating GH and/or IGF‐1 tonicity in the regulation of mammalian aging rate and lifespan.…”