Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans.

Fasting has emerged as a potent means of preserving tissue function with age in multiple model organisms. However, our understanding of the relationship between food removal and long-term health is incomplete. Here, we demonstrate that in the nematode worm Caenorhabditis elegans, a single period of early-life fasting is sufficient to selectively enhance HSF-1 activity, maintain proteostasis capacity and promote longevity without compromising fecundity. These effects persist even when food is returned, and are dependent on the mitochondrial sirtuin, SIR-2.2 and the H3K27me3 demethylase, JMJD-3.1. We find that increased HSF-1 activity upon fasting is associated with elevated SIR-2.2 levels, decreased mitochondrial copy number and reduced H3K27me3 levels at the promoters of HSF-1 target genes. Furthermore, consistent with our findings in worms, HSF-1 activity is also enhanced in muscle tissue from fasted mice, suggesting that the potentiation of HSF-1 is a conserved response to food withdrawal.

Distinct patterns of proteostasis network gene expression are associated with different prognoses in melanoma patients.

The proteostasis network (PN) is a collection of protein folding and degradation pathways that spans cellular compartments and acts to preserve the integrity of the proteome. The differential expression of PN genes is a hallmark of many cancers, and the inhibition of protein quality control factors is an effective way to slow cancer cell growth. However, little is known about how the expression of PN genes differs between patients and how this impacts survival outcomes. To address this, we applied unbiased hierarchical clustering to gene expression data obtained from primary and metastatic cutaneous melanoma (CM) samples and found that two distinct groups of individuals emerge across each sample type. These patient groups are distinguished by the differential expression of genes encoding ATP-dependent and ATP-independent chaperones, and proteasomal subunits. Differences in PN gene expression were associated with increased levels of the transcription factors, MEF2A, SP4, ZFX, CREB1 and ATF2, as well as markedly different survival outcomes. However, surprisingly, similar PN alterations in primary and metastatic samples were associated with discordant survival outcomes in patients. Our findings reveal that the expression of PN genes demarcates CM patients and highlights several new proteostasis sub-networks that could be targeted for more effective suppression of CM within specific individuals.

Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.

The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.

Autophagy in healthy aging and disease.

Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.

The importance of long-lived proteins: Not just nuclear anymore.

The significance of mitochondrial long-lived proteins (mitoLLPs) to tissue health has remained mysterious for over a decade. In this issue of Developmental Cell, Krishna et al. demonstrate that mitochondrial lifetimes are highly heterogeneous and that mitoLLPs promote respiratory capacity by facilitating supercomplex assembly within the electron transport chain.

A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse.

The loss of protein homeostasis (proteostasis) is a primary driver of age-related tissue dysfunction. Recent studies have revealed that the failure of proteostasis with age is triggered by developmental and reproductive cues that repress the activity of proteostasis-related pathways in early adulthood. In Caenorhabditis elegans, reduced mitochondrial electron transport chain (ETC) function during development can override signals that promote proteostasis collapse in aged tissues. However, it is unclear precisely how these beneficial effects are mediated. Here, we reveal that in response to ETC impairment, the PP2A complex generates a dephosphorylated, mitochondrial stress-specific variant of the transcription factor HSF-1. This results in the selective induction of small heat shock proteins in adulthood, thereby protecting against age-related proteostasis collapse. We propose that mitochondrial signals early in life can protect the aging cytosolic proteome by tailoring HSF-1 activity to preferentially drive the expression of non-ATP-dependent chaperones.

Proteostasis and longevity: when does aging really begin?

Aging is a complex process regulated by multiple cellular pathways, including the proteostasis network. The proteostasis network consists of molecular chaperones, stress-response transcription factors, and protein degradation machines that sense and respond to proteotoxic stress and protein misfolding to ensure cell viability. A loss of proteostasis is associated with aging and age-related disorders in diverse model systems, moreover, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan and suppress age-related disease. However, our understanding of the relationship between aging, proteostasis, and the proteostasis network remains unclear. Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.

Contesting the dogma of an age-related heat shock response impairment: implications for cardiac-specific age-related disorders.

Ageing is associated with the reduced performance of physiological processes and has been proposed as a major risk factor for disease. An age-related decline in stress response pathways has been widely documented in lower organisms. In particular, the heat shock response (HSR) becomes severely compromised with age in Caenorhabditis elegans. However, a comprehensive analysis of the consequences of ageing on the HSR in higher organisms has not been documented. We used both HS and inhibition of HSP90 to induce the HSR in wild-type mice at 3 and 22 months of age to investigate the extent to which different brain regions, and peripheral tissues can sustain HSF1 activity and HS protein (HSP) expression with age. Using chromatin immunoprecipitation, quantitative reverse transcription polymerase chain reaction, western blotting and enzyme linked immunosorbent assay (ELISA), we were unable to detect a difference in the level or kinetics of HSP expression between young and old mice in all brain regions. In contrast, we did observe an age-related reduction in chaperone levels and HSR-related proteins in the heart. This could result in a decrease in the protein folding capacity of old hearts with implications for age-related cardiac disorders.

Huntington's disease: underlying molecular mechanisms and emerging concepts.

Huntington's disease (HD) is a progressive neurodegenerative disorder for which no disease modifying treatments exist. Many molecular changes and cellular consequences that underlie HD are observed in other neurological disorders, suggesting that common pathological mechanisms and pathways may exist. Recent findings have enhanced our understanding of the way cells regulate and respond to expanded polyglutamine proteins such as mutant huntingtin. These studies demonstrate that in addition to effects on folding, aggregation, and clearance pathways, a general transcriptional mechanism also dictates the expression of polyglutamine proteins. Here, we summarize the key pathways and networks that are important in HD in the context of recent therapeutic advances and highlight how their interplay may be of relevance to other protein folding disorders.

Suppression of protein aggregation by chaperone modification of high molecular weight complexes.

Protein misfolding and aggregation are associated with many neurodegenerative diseases, including Huntington's disease. The cellular machinery for maintaining proteostasis includes molecular chaperones that facilitate protein folding and reduce proteotoxicity. Increasing the protein folding capacity of cells through manipulation of DNAJ chaperones has been shown to suppress aggregation and ameliorate polyglutamine toxicity in cells and flies. However, to date these promising findings have not been translated to mammalian models of disease. To address this issue, we developed transgenic mice that over-express the neuronal chaperone HSJ1a (DNAJB2a) and crossed them with the R6/2 mouse model of Huntington's disease. Over-expression of HSJ1a significantly reduced mutant huntingtin aggregation and enhanced solubility. Surprisingly, this was mediated through specific association with K63 ubiquitylated, detergent insoluble, higher order mutant huntingtin assemblies that decreased their ability to nucleate further aggregation. This was dependent on HSJ1a client binding ability, ubiquitin interaction and functional co-operation with HSP70. Importantly, these changes in mutant huntingtin solubility and aggregation led to improved neurological performance in R6/2 mice. These data reveal that prevention of further aggregation of detergent insoluble mutant huntingtin is an additional level of quality control for late stage chaperone-mediated neuroprotection. Furthermore, our findings represent an important proof of principle that DNAJ manipulation is a valid therapeutic approach for intervention in Huntington's disease.

Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease.

Huntington disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. Previous studies have proposed that activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1) may be of therapeutic benefit. However, the effect of disease progression on the HSR and the therapeutic potential of this pathway are currently unknown. Here, we used a brain-penetrating HSP90 inhibitor and physiological, molecular, and behavioral readouts to demonstrate that pharmacological activation of HSF1 improves huntingtin aggregate load, motor performance, and other HD-related phenotypes in the R6/2 mouse model of HD. However, the beneficial effects of this treatment were transient and diminished with disease progression. Molecular analyses to understand the transient nature of these effects revealed altered chromatin architecture, reduced HSF1 binding, and impaired HSR accompanied disease progression in both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. Taken together, our findings reveal that the HSR, a major inducible regulator of protein homeostasis and longevity, is disrupted in HD. Consequently, pharmacological induction of HSF1 as a therapeutic approach to HD is more complex than was previously anticipated.