All That Glitters...

You may recall the recent claims regarding a new aging gene named BubR1:

Researchers have discovered another regulatory gene (named BubR1) involved in the aging process. "Mutant mice with low amounts of BubR1 protein live five times shorter than normal mice. They also develop a variety of age-related disorders at a very young age. This prompted us to investigate whether BubR1 protein levels go down as normal mice age naturally -- which is indeed what we found ... we believe it is the decline of this protein with time that may trigger some of the physiological effects of ageing."

Michael Rae sent me an e-mail (with references) to comment on this item. Scroll down for the plain English conclusions if you are not following the science.

Wait... wait ... haven't I heard this one before?

"Here we show that [homozygous knock-in mice that express a [defective] ... mtDNA polymerase develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals." (1)

"A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. ...The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases." (2)

"Absence of Ku80 results in increased sensitivity to ionizing radiation, defective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence...." (3)

" The senescence-accelerated mouse (SAM) has been under development by our research team at Kyoto University since 1970 through selective inbreeding of the AKR/J strain ... At present, there are 12 lines of SAM ... Data from survival curves, the Gompertzian function and the grading score of senescence, together with growth patterns of body weight of these SAMP and SAMR mice revealed that the characteristic feature of aging common to all SAMP mice is "accelerated senescence": early onset and irreversible advance of senescence manifested by several signs and gross lesions such as the loss of normal behavior, various skin lesions, increased lordokyphosis, etc., after a period of normal development. Routine postmortem examinations and the pathobiological features revealed by systematically designed studies have shown several pathologic phenotypes, which are often characteristic enough to differentiate among the various SAM strains: senile amyloidosis ... secondary amyloidosis ... immunoblastic lymphoma ... histiocytic sarcoma ... ovarian cysts ... impaired immune response ... hyperinflation of the lungs ... hearing impairment ... degenerative temporomandibular joint disease ... senile osteoporosis ... deficits in learning and memory ... cataracts ... and brain atrophy ... These are all age-associated pathologies, the incidence and severity of which increase with advancing age." (4)

"Until you show me that you can postpone aging, I don't know that you've done anything," sniffs Michael R. Rose, geneticist at the University of California. "A lot of people can kill things off sooner, by screwing around with various mechanisms, but to me that's like killing mice with hammers -- it doesn't show that hammers are related to aging." (5)

1: Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. PMID: 15164064 [PubMed - indexed for MEDLINE]

2. Nature 1997 Nov 6;390(6655):45-51 Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. PMID: 9363890 [PubMed - indexed for MEDLINE]

3. Mol Cell Biol 2000 Jun;20(11):3772-80 Analysis of ku80-mutant mice and cells with deficient levels of p53. Lim DS, Vogel H, Willerford DM, Sands AT, Platt KA, Hasty P. PMID: 10805721

4. Takeda T. [Senescence-accelerated mouse (SAM): with special reference to age-associated pathologies and their modulation] Nippon Eiseigaku Zasshi. 1996 Jul;51(2):569-78. Review. Japanese. PMID: 8783874 [PubMed - indexed for MEDLINE]


So in essence, it is far too soon to jump to conclusions regarding any relationship between the aging process and the BubR1 gene - just because it looks like accelerated aging doesn't necessarily mean it is accelerated aging. More research is needed, as always.


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