Calorie Restriction Extends Life in Part via Endoplasmic Reticulum Hormesis

The endoplasmic reticulum is a cellular component involved in protein synthesis in cells, finalizing these molecules for use by folding them correctly. When the endoplasmic reticulum becomes cluttered with work in progress, or otherwise slowed down, this state is called endoplasmic reticulum stress. This triggers the unfolded protein response (UPR) to clear out any problem molecules and restore function. Researchers here show that mild endoplasmic reticulum stress and consequent UPR activation is one of the mechanisms by which calorie restriction improves health and tissue function, thereby extending life in short-lived species. We might compare this with what is known of the ability of calorie restriction to upregulate the cellular maintenance processes of autophagy, which serve an analogous purpose in clearing out damaged proteins and structures elsewhere in the cell, thereby maintaining a better cell state and function.

The endoplasmic reticulum (ER) deteriorates with age and fails to mount an effective stress response against misfolded proteins (UPRER), leading to protein folding disorders. Proteostasis collapse has long been associated with incidences of various diseases of protein aggregation. The catastrophic collapse of cellular proteostasis marks the commencement of the aging process. Thus, interventions that can delay the onset of the collapse has positive effects on health and longevity. Here, we show that dietary restriction (DR) effectively delays proteostasis collapse by maintaining robust UPRER and ER-associated degradation (ERAD) during adulthood, leading to increased life span. This is partially mediated by a sublethal dose of ER stress early during development that primes the ER for better function later in life. We also show that the mechanism maybe conserved in a mammalian cell culture model of protein aggregation. Since a sublethal ER stress generated by DR is able to confer health and life span benefits at adulthood, this mechanism may be categorized as hormesis.

DR has long been argued as a case of hormesis. While DR confers health and life span benefits, extended periods of DR or starvation may be detrimental. Even in C. elegans, DR produces a typical bell-shaped curve with ad libitum and least fed worms showing no life span benefits. Incidentally, the mechanisms of hormesis in case of DR mostly point toward mitochondrial metabolism. Glucose restriction, another mode of DR that also increases life span, works through a process of mitohormesis involving ROS-mediated up-regulation of cellular detoxification machinery. Additionally, lowering insulin-IGF1 signaling that is akin to reduced glucose metabolism requires mitohormesis to increase life span. Although, IRE-1 was found to be involved in life span regulation during DR, the mechanism was not linked to ER hormesis. Our study now elucidates how ER hormesis functions during DR, adding to the list of known mechanisms by which the conserved life span-extending intervention of diet restriction works.

We show that exposing worms to an early transient ER stress is able to increase life span and improve proteostasis in adulthood by the process of ER hormesis. It appears that a cellular memory is created by the sublethal ER stress during development that helps maintain a prolongevity transcriptional status. In support of this, we observe that the expression of the ERAD genes are increased early in eat-2 mutant worms and maintained into adulthood, even when the basal ER stress is low during DR. In future, the nature of the memory needs to be deciphered. We have shown here that DR as well ER hormesis prevents decline of UPRER efficiency that occurs with age. We observe that the basal ER stress levels are lower and that the organism can mount a robust UPRER when challenged.

The FOXA transcription factor PHA-4 plays a central role in DR-mediated longevity in C. elegans. It appears that the PHA-4 controls many prolongevity aspects of DR. It transcriptionally regulates the expression of genes coding for chromatin modifiers required for modulation of gene expression, xenobiotic detoxification pathway components, the superoxide dismutase system, as well as those involved in the splicing and nonsense-mediated decay pathway. In this study, we show that PHA-4 regulates the expression of the ERAD component genes, the transient UPRER, as well as modulates UPRER at adulthood. These finding show that the transcription factor controls diverse aspects of the regulatory network that provides prolongevity benefits of DR, qualifying as the central regulator of this process.



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