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Content archived on 2024-05-29

Is heat shock protein mediated protection against ageing and protein oxidation tissue specific?

Final Activity Report Summary - PROT.OX. AND HSPS (Is heat shock protein mediated protection against ageing and protein oxidation tissue specific?)

Animal ageing is accompanied by increased levels of oxidised and otherwise damaged proteins. The genetic interventions aimed at increasing the capacity of organisms to cope with such damage were, in some cases, demonstrated to extend life span. For example, the mitochondrial chaperone Hsp22 of drosophila melanogaster extended the life span of the flies when overproduced.

In this project I found that Hsp22 was unique among the analysed chaperones in that no other chaperone displayed such a massive increase in its levels during ageing, specifically in the flies’ head. This accumulation of Hsp22 in the ageing head was accompanied by a reduction in the levels of oxidatively modified proteins. However, these two phenomena did not appear to be linked since overproduction of Hsp22 failed to reduce damage levels, and dietary restriction (DR), which also extended the life span, resulted in reduced protein damage without elevating Hsp22. Furthermore, the DR-experiment revealed that physiological age seemed to be an important factor for Hsp22 regulation, since its levels increased further close to the time of death independently of chronological age. Thus, it appeared that Hsp22-dependent and DR-dependent life span extensions acted on separate pathways.

The analysis of protein damage and chaperone levels revealed that different body parts and tissues aged differently. Most interestingly, the abdomen of female, but not male flies, displayed a clear increase in damage upon ageing, whereas damage in the torace increased only modestly and actually declined in the ageing head, as mentioned above. However, all body parts responded to DR by a reduction in protein damage, which occurred without any significant increase in chaperone levels, proteasome subunit levels or activity. Another interesting effect of DR was a reduction in the levels of active caspase subunits, suggesting that DR might affect the cells propensity to enter apoptotic pathways during ageing.

One of the perhaps most interesting findings was that fly eggs, unexpectedly, displayed similar levels of oxidised proteins as the adult mother but eliminated this damage upon embryonic development following fertilisation. In comparison to adult flies, the eggs exhibited markedly higher levels of proteasomal subunits. However, this elevated capacity for proteolysis and damage removal appeared to be set into action only after the fertilisation of eggs and the progress of early development, as seen by an increased 20S proteasomal activity and a decline in the concentration of damaged proteins subsequent to the onset of development. This result was relevant to the question of how the level of protein damage was set to zero in newborn offspring. One hypothesis, the germ-line conservation theory, assumed that the germ line was protected in the sense that damage was segregated so that eggs were kept free from damage when produced. Another hypothesis, not mutually exclusive, pointed to germ cells being provided with superior means to rid themselves of damaged proteins but not doing so until the embarking on embryonic development. This could ensure that resources for damage elimination were only invested in the germ cells that would become progeny. As described above, the results of this project lent some support to this latter hypothesis.

Finally, an important technical achievement resulting from this project was the protocol I developed, which allowed for in situ carbonylation detection in whole mount embryos.