Proteasome activation delays aging and progression of age-related diseases
Efstathios S. Gonos
National Hellenic Research Foundation,
Institute of Biology, Medicinal Chemistry & Biotechnology, Athens, Greece
e-mail: [email protected]
Aging and longevity are two multifactorial biological phenomena whose knowledge at molecular level is still limited. We have studied proteasome function in replicative senescence and cell survival (Mol Aspects Med 35, 1-71; Ageing Res Rev 23, 37-55).
We have observed reduced levels of proteasome content and activities in senescent cells due to the down-regulation of the catalytic subunits of the 20S complex (J Biol Chem 278, 28026-28037). In support, partial inhibition of proteasomes in young cells by specific inhibitors induces premature senescence which is p53 dependent (Aging Cell 7, 717-732). Stable over-expression of catalytic subunits or POMP resulted in enhanced proteasome assembly and activities and increased cell survival following treatments with various oxidants. Importantly, the developed “proteasome activated” human fibroblasts cell lines exhibit a delay of senescence by approximately 20% (J Biol Chem 280, 11840-11850; J Biol Chem 284, 30076-30086). Similar proteasome activation in human mesenchymal stem cells not only increases their lifespan, but also enhances stemness significantly (Free Rad Biol Med 103, 226-235). Moreover, additional findings indicate that the recorded proteasome activation by many inducers is Nrf2-dependent (J Biol Chem 285, 8171-8184). Finally, we provide evidence that proteasome activation is an evolutionary conserved mechanism, as it can delay aging in vivo and, importantly, it also confers deceleration of aggregation-related pathologies, such as Alzheimer’s or Huntington’s diseases (FASEB J 29, 611-622). Given these findings, recent work has identified a proteasome activator that decelerates aging and Alzheimer’s disease progression (Antiox Redox Signal 25, 855-869).
There are no financial interests to disclose
National Hellenic Research Foundation,
Institute of Biology, Medicinal Chemistry & Biotechnology, Athens, Greece
e-mail: [email protected]
Aging and longevity are two multifactorial biological phenomena whose knowledge at molecular level is still limited. We have studied proteasome function in replicative senescence and cell survival (Mol Aspects Med 35, 1-71; Ageing Res Rev 23, 37-55).
We have observed reduced levels of proteasome content and activities in senescent cells due to the down-regulation of the catalytic subunits of the 20S complex (J Biol Chem 278, 28026-28037). In support, partial inhibition of proteasomes in young cells by specific inhibitors induces premature senescence which is p53 dependent (Aging Cell 7, 717-732). Stable over-expression of catalytic subunits or POMP resulted in enhanced proteasome assembly and activities and increased cell survival following treatments with various oxidants. Importantly, the developed “proteasome activated” human fibroblasts cell lines exhibit a delay of senescence by approximately 20% (J Biol Chem 280, 11840-11850; J Biol Chem 284, 30076-30086). Similar proteasome activation in human mesenchymal stem cells not only increases their lifespan, but also enhances stemness significantly (Free Rad Biol Med 103, 226-235). Moreover, additional findings indicate that the recorded proteasome activation by many inducers is Nrf2-dependent (J Biol Chem 285, 8171-8184). Finally, we provide evidence that proteasome activation is an evolutionary conserved mechanism, as it can delay aging in vivo and, importantly, it also confers deceleration of aggregation-related pathologies, such as Alzheimer’s or Huntington’s diseases (FASEB J 29, 611-622). Given these findings, recent work has identified a proteasome activator that decelerates aging and Alzheimer’s disease progression (Antiox Redox Signal 25, 855-869).
There are no financial interests to disclose
