Biology subjects

Samuelson, A. V.

Publications and source records attributed to Samuelson, A. V..

2 recordsLinked to original sources

bioRxiv2023

The C. elegans Myc-family of transcription factors coordinate a dynamic adaptive response to dietary restriction.

Dietary restriction (DR), the process of decreasing overall food consumption over an extended period of time, has been shown to increase longevity across evolutionarily diverse species and delay the onset of age-associated diseases in humans. In Caenorhabditis elegans, the Myc-family transcription factors (TFs) MXL-2 (Mlx) and MML-1 (MondoA/ChREBP), which function as obligate heterodimers, and PHA-4 (orthologous to forkhead box transcription factor A) are both necessary for the full physiological benefits of DR. However, the adaptive transcriptional response to DR and the role of MML-1::MXL-2 and PHA-4 remains elusive. We identified the transcriptional signature of C. elegans DR, using the eat-2 genetic model, and demonstrate broad changes in metabolic gene expression in eat-2 DR animals, which requires both mxl-2 and pha-4. While the requirement for these factors in DR gene expression overlaps, we found many of the DR genes exhibit an opposing change in relative gene expression in eat-2;mxl-2 animals compared to wild-type, which was not observed in eat-2 animals with pha-4 loss. We further show functional deficiencies of the mxl-2 loss in DR outside of lifespan, as eat-2;mxl-2 animals exhibit substantially smaller brood sizes and lay a proportion of dead eggs, indicating that MML-1::MXL-2 has a role in maintaining the balance between resource allocation to the soma and to reproduction under conditions of chronic food scarcity. While eat-2 animals do not show a significantly different metabolic rate compared to wild-type, we also find that loss of mxl-2 in DR does not affect the rate of oxygen consumption in young animals. The gene expression signature of eat-2 mutant animals is consistent with optimization of energy utilization and resource allocation, rather than induction of canonical gene expression changes associated with acute metabolic stress -such as induction of autophagy after TORC1 inhibition. Consistently, eat-2 animals are not substantially resistant to stress, providing further support to the idea that chronic DR may benefit healthspan and lifespan through efficient use of limited resources rather than broad upregulation of stress responses, and also indicates that MML-1::MXL-2 and PHA-4 may have different roles in promotion of benefits in response to different pro-longevity stimuli.

genetics↗

bioRxiv2022

Neuroendocrine control of the proteostatic network by HPK-1 delays aging

The nervous system systemically coordinates proteostasis to delay organismal aging. However, the neuronal regulatory mechanisms that coordinate cellular anti-aging programs across tissue and cell-types are relatively unknown. In this work, we identify the homeodomain-interacting protein kinase (HPK-1), a transcriptional cofactor, as a novel neuronal component of the proteostatic network: its overexpression produces a paracrine signal to hyper-induce molecular chaperones and a neuroendocrine signal to induce autophagy in peripheral tissues. Neuronal HPK-1 signaling improves proteostasis in distal tissues through neurotransmitters. These pro-longevity modalities are independently regulated within serotonergic and GABAergic neurons, respectively, through distinct adaptive responses, either of which improve proteostasis in a cell non-autonomous manner. Serotonergic HPK-1 activity amplifies the heat shock response and protects the proteome from acute stress, without altering longevity. Conversely, increased GABAergic HPK-1 activity is sufficient to induce autophagy and extend longevity, without altering acute stress survival. Consistently, GABAergic neurons, but not serotonin, is essential for the cell non-autonomous induction of autophagy by neuronal HPK-1. These findings provide novel insight into how the nervous system partitions and coordinates unique adaptive response pathways to delay organismal aging, and reveals a key role for neuronal HPK-1 in regulating the proteostatic network throughout an intact metazoan animal. Significance StatementAging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network in peripheral tissues. How neuronal signaling mechanisms are primed, relayed through an organism, and specific responses are initiated in receiving cell types remain poorly understood. We have discovered that the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) is a novel transcriptional effector that functions within two distinct neuronal cell-types to non-autonomously regulate divergent components of the proteostatic network to enhance stress resistance, improve proteostasis and delay aging.

genetics↗