Proteostasis collapse is a driver of cell aging and death

Santra, Mantu; Dill, Ken A.; Graff, Adam M.R. de

doi:10.1073/pnas.1906592116

Cited by 141 publications

(97 citation statements)

References 83 publications

(139 reference statements)

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“…proteinopathies and thus neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (141,142). The proteostasis decline is one of the hallmarks of aging (1,143) and this decline can be explained by increased generation of oxidative damage within the cells (144).…”

Section: Proteostasis and Agingmentioning

confidence: 99%

“…This quality control system is known as proteostasis and its failures rely on increased levels of protein aggregates, which contribute to the development of proteinopathies and thus neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis ( 141 , 142 ). The proteostasis decline is one of the hallmarks of aging ( 1 , 143 ) and this decline can be explained by increased generation of oxidative damage within the cells ( 144 ).…”

Section: Proteostasis and Agingmentioning

confidence: 99%

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Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

et al. 2020

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The aging process is characterized by a series of molecular and cellular changes over the years that could culminate in the deterioration of physiological parameters important to keeping an organism alive and healthy. Physical exercise, defined as planned, structured and repetitive physical activity, has been an important force to alter physiology and brain development during the process of human beings' evolution. Among several aspects of aging, the aim of this review is to discuss the balance between two vital cellular processes such as autophagy and apoptosis, based on the fact that physical exercise as a non-pharmacological strategy seems to rescue the imbalance between autophagy and apoptosis during aging. Therefore, the effects of different types or modalities of physical exercise in humans and animals, and the benefits of each of them on aging, will be discussed as a possible preventive strategy against neuronal death.

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Section: Proteostasis and Agingmentioning

confidence: 99%

Section: Proteostasis and Agingmentioning

confidence: 99%

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

et al. 2020

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“…Because age is the most prominent "risk factor" for a wide range of metabolic diseases, such as diabetes, heart disease, neurodegeneration, and most cancers [3,4], it is critical to understand the cellular and molecular changes that accumulate and lead to these diseases. Cells and tissues display common perturbations across age, such as a diminished capacity for proteostasis [5,6] and the accumulation of mitochondrial defects [7]. These common endpoints are clearly recognized, but there is a dramatic diversity of the timelines connecting these mechanisms to chronological age ("lifespan") and biological age ("healthspan") across individuals, let alone across organisms.…”

Section: Introductionmentioning

confidence: 99%

Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

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Pfister

Roy

et al. 2020

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Systems biology approaches often use networks of gene expression and metabolite data to identify regulatory factors and pathways connected with phenotypic variance. Separating upstream causal mechanisms, downstream biomarkers, and incidental correlations remains a significant challenge, yet it is essential for designing mechanistic experiments. To address this, we first designed a population following 2157 individual mice from 89 isogenic strains of BXD mice across their lifespans to identify molecular interactions between genotype, environment, age (GxExA) and metabolic fitness. Each strain was separated into two cohorts, fed low fat (6% cal/fat) or high fat (60% cal/fat) diets. One-third of individuals (662) were sacrificed at ~6, 12, 18, or 24 months-of-age, with the remainder monitored until natural death. Transcriptome, proteome, and metabolome profiles were generated from liver samples. These multi-omic measurements were deconvolved into metabolic networks, where we observed varying network connectivity as a function of GxExA. The multiple independent study variables permitted causal inference analysis for the network variants using stability selection. This calculates the strength and directionality of the interactions between molecular measurements and metabolic networks as a function of age, diet, and genotype, and assigns each gene a score for its relative position to the target pathway. At 1% FDR, 94% of novel connections were stable across age and diet, such as the connection between Rdh11 with cholesterol biosynthesis and Mut with mitochondrial translation. 6% of discovered candidate genes were unstable, indicating a clear causal relationship between the segregating independent variable, the gene, and the pathway. For instance, age drives variation in proteasomal genes (e.g. Psmb3, Psmb4), which in turn drive changes in the mitochondrial ribosome. Conversely, COX7A2L malformation drives variation in OXPHOS genes, but both are downstream of changes in mitochondrial translation. Finally, we examined all data for connections with the longevity and known longevity-related pathways, identifying several dozen novel candidate genes. Specific C. elegans orthologs for the top two candidates, Ctsd and St7, were knocked down with RNAi and found to reduce longevity both in wildtype worms and in mutant long-lived strains.

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“…An entirely different issue is survival during starvation, where senescence has recently been proposed as an adaptive strategy based on the finding that starving E. coli cells, like nonstarving humans, follow the Gompertz law of mortality (85). However, the Gompertz law has been shown to arise from a variety of processes, including tumor growth, growth of batch cultures, and genetic or acquired susceptibilities to death (86)(87)(88)(89)(90)(91), so no mechanistic conclusions can be drawn from finding that mortality follows the phenomenological Gompertz law.…”

Section: Discussionmentioning

confidence: 99%

Damage Repair versus Aging in an Individual-Based Model of Biofilms

et al. 2020

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The extent of senescence due to damage accumulation—or aging—is evidently evolvable as it differs hugely between species and is not universal, suggesting that its fitness advantages depend on life history and environment. In contrast, repair of damage is present in all organisms studied. Despite the fundamental trade-off between investing resources into repair or into growth, repair and segregation of damage have not always been considered alternatives. For unicellular organisms, unrepaired damage could be divided asymmetrically between daughter cells, leading to senescence of one and rejuvenation of the other. Repair of “unicells” has been predicted to be advantageous in well-mixed environments such as chemostats. Most microorganisms, however, live in spatially structured systems, such as biofilms, with gradients of environmental conditions and cellular physiology as well as a clonal population structure. To investigate whether this clonal structure might favor senescence by damage segregation (a division-of-labor strategy akin to the germline-soma division in multicellular organisms), we used an individual-based computational model and developed an adaptive repair strategy where cells respond to their current intracellular damage levels by investing into repair machinery accordingly. Our simulations showed that the new adaptive repair strategy was advantageous provided that growth was limited by substrate availability, which is typical for biofilms. Thus, biofilms do not favor a germline-soma-like division of labor between daughter cells in terms of damage segregation. We suggest that damage segregation is beneficial only when extrinsic mortality is high, a degree of multicellularity is present, and an active mechanism makes segregation effective. IMPORTANCE Damage is an inevitable consequence of life. For unicellular organisms, this leads to a trade-off between allocating resources into damage repair or into growth coupled with segregation of damage upon cell division, i.e., aging and senescence. Few studies considered repair as an alternative to senescence. None considered biofilms, where the majority of unicellular organisms live, although fitness advantages in well-mixed systems often turn into disadvantages in spatially structured systems such as biofilms. We compared the fitness consequences of aging versus an adaptive repair mechanism based on sensing damage, using an individual-based model of a generic unicellular organism growing in biofilms. We found that senescence is not beneficial provided that growth is limited by substrate availability. Instead, it is useful as a stress response to deal with damage that failed to be repaired when (i) extrinsic mortality was high; (ii) a degree of multicellularity was present; and (iii) damage segregation was effective.

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Proteostasis collapse is a driver of cell aging and death

Cited by 141 publications

References 83 publications

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

Damage Repair versus Aging in an Individual-Based Model of Biofilms

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