Deletion of pregnancy-associated plasma protein-A (PAPP-A) is one of a number of genetic alterations that have been used to produced lineages of long-lived mice. For researchers interested in translating this sort of discovery into treatments that might modestly slow human aging, an important question is whether the mice live longer because this alteration was present throughout development and childhood, or whether the effects on life span are determined over the course of adult life. Only in the latter case would researchers be able to proceed with any confidence to work on the basis for a human treatment. To further investigate the basis for enhanced longevity in mice lacking PAPP-A, researchers have now used a form of gene therapy to delete PAPP-A in adult mice, an approach we should expect to see applied in the years ahead to all of the genetic approaches that extend life in mice. Here, they report on the results.
To date, the only known function of pregnancy-associated plasma protein-A (PAPP-A) is to enhance local insulin-like growth factor (IGF) availability for receptor activation through cleavage of inhibitory IGF binding proteins. As reduced IGF signaling has been shown to increase life span in a wide variety of species, we postulated that loss of PAPP-A would suppress IGF receptor signaling and extend life span. This was proven true in that both male and female PAPP-A knockout (KO) mice lived significantly longer than their wild-type littermates. The PAPP-A KO mice were also resistant to the development of several age-related diseases, such as atherosclerosis.
However, these mice were generated through homologous recombination in embryonic stem cells. To distinguish the impact of PAPP-A deficiency in the adult from that during fetal and early postnatal development, we developed a mouse model suitable for tamoxifen (Tam)-inducible, Cre recombinase-mediated excision of the PAPP-A gene. In an atherosclerosis-prone mouse model, Tam administration in adult mice inhibited established atherosclerotic plaque progression by 70%. In this study, we sought to answer the question of whether conditional reduction of PAPP-A gene expression in adult mice would result in extended life span.
Female mice homozygous for floxed PAPP-A (fPAPP-A) and either positive (pos) or negative (neg) for Tam-Cre were used in the life span study. fPAPP-A/neg and fPAPP-A/pos mice had similar weights at the start of the experiment and showed equivalent weight gain up to 17 months of age. We found that fPAPP-A/pos mice had a significant extension of life span. The median life span was increased by 21% for fPAPP-A/pos compared to fPAPP-A/neg mice. Mortality in life span quartiles indicates that the proportion of deaths of fPAPP-A/pos mice were lower than fPAPP-A/neg mice at young adult ages and higher than fPAPP-A/neg mice at older ages. This study is the first to show that downregulation of PAPP-A expression in adult mice can significantly extend life span.
Importantly, this beneficial longevity phenotype is distinct from the dwarfism of long-lived PAPP-A KO, Ames dwarf, Snell dwarf and growth hormone receptor (GHR) KO mice with germ-line mutations. Thus, downregulation of PAPP-A expression joins other treatment regimens, such as resveratrol, rapamycin and dietary restriction, which can extend life span when started in mice as adults. In a recent study, inducible knockdown of the GHR in young adult female mice increased maximal, but not median, life span. Tissue-specific PAPP-A KO models would provide insight into the tissues and organs that contribute to extended life span and healthspan.