title: The effect of aging on mitochondrial and cytosolic hepatic intrinsic death pathway and apoptosis associated proteins in Fischer 344 rats.
abstract: Apoptosis is increased in the liver in old age and is a common pathological feature of liver disease. The mitochondria play a key role in regulating apoptosis via the intrinsic death pathway. As the effect of aging on this pathway is unclear, we aimed to characterize the impact of aging on the hepatic intrinsic death pathway and apoptosis. Livers from young adult (6.6 ± 0.3 months, n = 9) and old (25.4 ± 0.7 months, n = 9) male Fischer 344 rats were extracted for cellular fractionation and immunobloting. In old age there were lower mitochondrial protein levels of pro-apoptotic BAK, BID, tBID and VDAC1 (p < 0.05) and of anti-apoptotic Bcl-2. Compared to young, old rats had lower cytosolic protein levels of pro-apoptotic BAX, BAK, BID, tBID and anti-apoptotic Bcl-xL (p < 0.05). BAK, Bcl-2 and Bcl-xL were found in the cytosol. Furthermore with old age, cytosolic protein levels of cytochrome C, AIF and cleaved caspase-9 did not change but activation of caspase-3, -6 and -7 increased (p < 0.05) and DNA fragmentation trended to increase. Our results suggest an age-related decline in the levels of a number of proteins involved in the intrinsic death pathway, an uncoupling of intermediate apoptosis signaling and increased cellular apoptosis in the liver in old age.
authors.affiliation: Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Sydney, NSW, Australia; Depts of Clinical Pharmacology and Aged Care, Royal North Shore Hosp, Sydney, NSW, Australia; Sydney Medical School, Univ of Sydney, Sydney, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Mach
authors.affiliation: Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Sydney, NSW, Australia; Depts of Clinical Pharmacology and Aged Care, Royal North Shore Hosp, Sydney, NSW, Australia.
authors.forename: Aniko
authors.initials: A
authors.lastname: Huizer-Pajkos
authors.affiliation: Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Sydney, NSW, Australia; Depts of Clinical Pharmacology and Aged Care, Royal North Shore Hosp, Sydney, NSW, Australia; Sydney Medical School, Univ of Sydney, Sydney, NSW, Australia.
authors.forename: Alice
authors.initials: A
authors.lastname: Kane
authors.affiliation: Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Sydney, NSW, Australia; Sydney Medical School, Univ of Sydney, Sydney, NSW, Australia; Gastroenterology Dept, Royal North Shore Hosp, Sydney, NSW, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Jones
authors.affiliation: Pathology Dept, Royal Prince Alfred Hosp, Sydney, NSW, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McKenzie
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Sydney Medical School, Univ of Sydney, Sydney, NSW, Australia; Ageing and Alzheimers Institute, Concord Hospital, Australia; Centre for Education and Research on Ageing, Concord Hospital and University of Sydney, Australia; ANZAC Research Institute, Concord Hospital and University of Sydney, Australia.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.affiliation: Sydney Medical School, Univ of Sydney, Sydney, NSW, Australia; Ageing and Alzheimers Institute, Concord Hospital, Australia; Centre for Education and Research on Ageing, Concord Hospital and University of Sydney, Australia; ANZAC Research Institute, Concord Hospital and University of Sydney, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.affiliation: Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Sydney, NSW, Australia; Depts of Clinical Pharmacology and Aged Care, Royal North Shore Hosp, Sydney, NSW, Australia; Sydney Medical School, Univ of Sydney, Sydney, NSW, Australia. Electronic address: sarah.hilmer@sydney.edu.au.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hilmer
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism* / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D011916:Rats, Inbred F344
chemical_list: D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins
keywords: Aging; Apoptosis; Intrinsic death pathway; Liver; Mitochondria