Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Abstract

Incomplete conclusion that mitochondrial protein synthesis rate is slower in the long-lived model Protein synthesis Protein synthesis ≥ Insightful conclusion that new mitochondrial proteins synthesized are allocated to maintaining/ replacing proteins in existing cells in the long-lived model Simultaneously measure mitochondrial protein synthesis and DNA Synthesis rate Protein synthesis Protein synthesis ≥ DNA synthesis DNA synthesis < Control mouse Long-lived mouse Measure mitochondrial protein synthesis rate only Control mouse Long-lived mouseAbstract Proteostasis is one of the seven "pillars of aging research" identified by the Trans-NIH Geroscience Initiative and loss of proteostasis is associated with aging and age-related chronic disease. Accumulated protein damage and resultant cellular dysfunction are consequences of limited protein repair systems and slowed protein turnover. When relatively high rates of protein turnover are maintained despite advancing age, damaged proteins are more quickly degraded and replaced, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides necessary mechanistic insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with a number of murine models of slowed aging shows that, compared to controls, energetic resources are directed more toward somatic maintenance and proteostasis, and away from cell growth and proliferation. In particular, slowed aging models are associated with heightened mechanisms of mitochondrial proteostatic maintenance. Taking cell proliferation into account may explain the paradoxical findings that aging itself and slowed aging interventions can both be characterized by slower rates of protein synthesis. Abstract figure legendProteostasis is one of the seven 'pillars of ageing research' identified by the Trans-NIH Geroscience Initiative, and loss of proteostasis is associated with ageing and age-related chronic disease. Maintenance of protein turnover represents an important mechanism for preserving proteome fidelity. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides critical insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with murine models of slowed ageing shows that mitochondrial proteostatic maintenance is a characteristic shared among these slowed ageing models.

Mitochondrial adaptations to exercise do not require Bcl2‐mediated autophagy but occur with BNIP3/Parkin activation

“…Protein synthesis and degradation pathways facilitate the turnover of mitochondrial proteins. Declines in skeletal muscle protein turnover rates are observed in metabolic diseases and with advancing age . Many metabolic and age‐associated pathological conditions are also associated with mitochondrial defects or dysfunction .…”

“…Declines in skeletal muscle protein turnover rates are observed in metabolic diseases [2][3][4] and with advancing age. 5,6 Many metabolic and age-associated pathological conditions are also associated with mitochondrial defects or dysfunction. 7,8 Endurance exercise training improves mitochondrial oxidative function and whole-body metabolic health, in part by increasing skeletal muscle mitochondrial abundance 9 mediated by increases in mitochondrial biogenesis.…”

Accumulation of “Old Proteins” and the Critical Need for MS‐based Protein Turnover Measurements in Aging and Longevity

“…When protein abundances change and steady state does not apply, it is unclear whether the effects are due to changes in protein synthesis or degradation. These cases require additional information and effort to account for these factors, such as accurate accounting of cell proliferation rates, using multiple labels, or other considerations . Some methods do not require additional effort but are restricted in their application, such as the ‘flooding dose’ approach, which is used to calculate protein synthesis rates but over a very acute (less than 30 minute) time period …”

“…These cases require additional information and effort to account for these factors, such as accurate accounting of cell proliferation rates, using multiple labels, or other considerations. [40][41][42][43][44][45] Some methods do not require additional effort but are restricted in their application, such as the 'flooding dose' approach, which is used to calculate protein synthesis rates but over a very acute (less than 30 minute) time period. [46] A number of powerful non-MS based approaches have also been employed in the determination of protein synthesis, degradation, and turnover rates.…”

Overview: the modulation of ageing through altered proteostasis

“…Therefore, it makes sense that the four speakers in the symposium approached the topic of proteostasis and ageing from distinctly different viewpoints. Three of the papers focus on the dynamic processes that regulate protein content – synthesis and breakdown (Drake & Yan, ; Hamilton & Miller, ; Sands et al . ).…”