Aging in mouse brain is a cell/tissue-level phenomenon exacerbated by proteasome loss.
Biological aging is often described by its phenotypic effect on individuals. Still, its causes are more likely found on the molecular level. Biological organisms can be considered as reliability-engineered, robust systems and applying reliability theory to their basic nonaging components, proteins, could provide insight into the aging mechanism. Reliability theory suggests that aging is an obligatory trade-off in a fault-tolerant system such as the cell which is constructed based on redundancy design. Aging is the inevitable redundancy loss of functional system components, that is proteins, over time. In our study, we investigated mouse brain development, adulthood, and aging from embryonic day 10 to 100 weeks. We determined redundancy loss of different protein categories with age using reliability theory. We observed a near-linear decrease of protein redundancy during aging. Aging may therefore be a phenotypic manifestation of redundancy loss caused by nonfunctional protein accumulation. This is supported by a loss of proteasome system components faster than dictated by reliability theory. This loss is highly detrimental to biological self-renewal and seems to be a key contributor to aging and therefore could represent a major target for therapies for aging and age-related diseases.
Mao
Lei
L
Institute for Human Genetics, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Römer
Irmgard
I
Nebrich
Grit
G
Klein
Oliver
O
Koppelstätter
Andrea
A
Hin
Sascha C
SC
Hartl
Daniela
D
Zabel
Claus
C
D000375:Aging / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D012044:Regression Analysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
D011506:Proteins; D020543:Proteome; D046988:Proteasome Endopeptidase Complex