Pregnancy-associated Plasma protein-A Deficiency Improves Survival of Mice on a High Fat Diet

Exp Gerontol. 2015 Oct;70:131-4. doi: 10.1016/j.exger.2015.08.007. Epub 2015 Aug 29.


Obesity is on the rise in westernized countries, and visceral obesity in particular is associated with enhanced risk of developing metabolic disease and accelerated aging. Various dietary restriction regimens have been shown to extend healthy lifespan in a variety of species. However, identification of alternative approaches that could be more acceptable to humans is actively being pursued. We have shown previously that mice deficient in pregnancy-associated plasma protein-A (PAPP-A) have an extended healthy lifespan on a regular chow diet. In this study, we determined the lifespan of PAPP-A knock-out (KO) and wild-type (WT) littermates fed a high fat diet (HFD) starting at 12 months of age. PAPP-A KO and WT mice had equivalent weight gain as measured over 25 weeks on HFD. However, PAPP-A KO mice on HFD had a significant increase in lifespan (P=0.018). Body composition and tissue pathology were assessed in a separate cohort of mice after 30 weeks on HFD. Percent body fat was equivalent in the two groups. However, there was a decrease in visceral fat depot weights and an increase in serum adiponectin levels in PAPP-A KO compared to WT mice. Major pathological differences were seen in kidney, heart and testes, with PAPP-A KO mice having little, if any, evidence of inflammation, mineralization, or degeneration in these tissues compared to WT mice. Thus, PAPP-A is a novel drug target with the potential to promote healthy longevity without a need for dietary restriction.

Keywords: Gene knock-out; High fat diet; Lifespan; Mouse model; Pregnancy-associated plasma protein-A.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / pathology
  • Aging / pathology
  • Animals
  • Body Composition / physiology
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Heart Diseases / etiology
  • Heart Diseases / pathology
  • Intra-Abdominal Fat / pathology
  • Kidney Diseases / etiology
  • Kidney Diseases / pathology
  • Longevity / physiology
  • Male
  • Mice, Knockout
  • Organ Size / physiology
  • Pregnancy-Associated Plasma Protein-A / deficiency*
  • Pregnancy-Associated Plasma Protein-A / genetics
  • Pregnancy-Associated Plasma Protein-A / physiology
  • Survival Analysis
  • Testicular Diseases / etiology
  • Testicular Diseases / pathology
  • Weight Gain / physiology


  • Pregnancy-Associated Plasma Protein-A