X-Message-Number: 24178 Date: Tue, 1 Jun 2004 19:23:39 -0700 (PDT) From: Doug Skrecky <> Subject: are mitochondria important in aging, or not? (From the two abstracts quotes below, one could reach diametrically opposite conclusions.) Physiol Genomics. 2003 Dec 16;16(1):29-37. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Mice heterozygous for the Sod2 gene (Sod2+/- mice) have been used to study the phenotype of life-long reduced Mn-superoxide dismutase (MnSOD) activity. The Sod2+/- mice have reduced MnSOD activity (50%) in all tissues throughout life. The Sod2+/- mice have increased oxidative damage as demonstrated by significantly elevated levels of 8-oxo-2-deoxyguanosine (8oxodG) in nuclear DNA in all tissues of Sod2+/- mice studied. The levels of 8oxodG in nuclear DNA increased with age in all tissues of Sod2+/- and wild-type (WT) mice, and at 26 mo of age, the levels of 8oxodG in nuclear DNA were significantly higher (from 15% in heart to over 60% in liver) in the Sod2+/- mice compared with WT mice. The level of 8oxodG was also higher in mitochondrial DNA isolated from liver and brain in Sod2+/- mice compared with WT mice. The increased oxidative damage to DNA in the Sod2+/- mice is associated with a 100% increase in tumor incidence (the number of mice with tumors) in old Sod2+/- mice compared with the old WT mice. However, the life spans (mean and maximum survival) of the Sod2+/- and WT mice were identical. In addition, biomarkers of aging, such as cataract formation, immune response, and formation of glycoxidation products carboxymethyl lysine and pentosidine in skin collagen changed with age to the same extent in both WT and Sod2+/- mice. Thus life-long reduction of MnSOD activity leads to increased levels of oxidative damage to DNA and increased cancer incidence but does not appear to affect aging. Reduced Mitochondrial Function Important Mechanism In Aging Scientists at the Karolinska Institute have found that changes in the "powerhouse" of cells, the mitochondria, play a key role in aging. The findings are being published in this week's issue of the journal Nature. Mitochondria, which provide energy to cells, have their own set of DNA. Mutations of mitochondrial DNA increase with age, but until now no one knew whether this is a result of aging or a cause of aging. New research findings now indicate that the latter is the case. Mice with a deficient capacity to correct mutations in mitochondrial DNA acquired an increased number of mutations and proved to age considerably earlier than normal. They lived an average of 10 to 12 months compared with the normal 2 or 3 years. These mice also developed several typical signs of premature aging, such as osteoporosis, weight loss, hair loss, anemia, reduced fertility, and heart muscle disorders. The findings reveal fundamental biological mechanisms that lie behind the aging process. This knowledge paves the way for the possibility of slowing down aging and treating pathological changes that arise in connection with aging by protecting mitochondrial DNA from damage. The article is published in Nature, May 27, 2004, pp. 417-423. It is illustrated by a picture on the cover of Nature and commentated by two scientists from the University of Washington, Seattle. Publication: Premature aging in mice expressing defective mitochondrial DNA polymerase Nature (2004) 429: 417-423, Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=24178