bims-minfam 2022-10-09 papers

Issue of 2022‒10‒09
three papers selected by
Ayesh Seneviratne
Western University

Aging Cell. 2022 Oct 05. e13721

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.

Rashpal S Dhillon, Yiming Amy Qin, Paul R van Ginkel, Vivian X Fu, James M Vann, Alexis J Lawton, Cara L Green, Fúlvia B Manchado-Gobatto, Claudio A Gobatto, Dudley W Lamming, Tomas A Prolla, John M Denu.

Mitochondrial NAD+ -dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/- ) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

Keywords: aerobic fitness; calorie restriction; fatty acid oxidation; fuel switching; lifespan; mitochondrial acetylation; mitochondrial respiration; sirtuins

DOI: https://doi.org/10.1111/acel.13721

Aging Cancer. 2022 Jun;3(2): 87-94

Cancer and aging: A call to action.

Dejana Braithwaite, Stephen Anton, Supriya Mohile, James DeGregori, Nancy Gillis, Daohong Zhou, Shirley Bloodworth, Marco Pahor, Jonathan Licht.

Background: The intersection of cancer and aging is an emerging public health challenge in developed countries because of the aging and expansion of the population.Aims: We convened a panel of experts to share their insights on this topic at the inaugural University of Florida Health Cancer Center's (UFHCC's) Cancer and Aging Symposium, which was held virtually in February 2022.
Methods: We featured presentations from four leading scientists, whose research spans multiple disciplines including basic science, translational research, geriatric oncology, and population science.
Results: Each speaker offered their unique perspective and insight on the intersection between cancer and aging and discussed their current and ongoing research in this field. In addition to this panel of experts, scientists from the National Institutes of Health and the National Cancer Institute, as well as a UFHCC-affiliated citizen scientist, shared their perspectives on strategies to move the field forward. Some of the key open questions and opportunities for future research offered by these presenters in aging and cancer include but are not limited to infusing health disparities research into the field of cancer and aging, assessing the value of geriatric assessment in identifying early vulnerabilities that may affect response to emerging cancer therapies in older patients, and assessing biological age and other biomarkers (e.g., clonal hematopoiesis) in relation to clinical endpoints and the development of primary, secondary, and tertiary cancer prevention interventions.
Conclusion: Research is needed to accelerate knowledge regarding the dynamic interplay of cancer and aging and optimize care in diverse older adults to achieve equity in cancer outcomes.

Keywords: aging; cancer; transdisciplinary science

DOI: https://doi.org/10.1002/aac2.12055

Front Physiol. 2022 ;13 997358

Mitochondrial fatty acid β-oxidation is important for normal osteoclast formation in growing female mice.

Priyanka Kushwaha, Nathalie S Alekos, Soohyun P Kim, Zhu Li, Michael J Wolfgang, Ryan C Riddle.

Skeletal remodeling is an energy demanding process that is linked to nutrient availability and the levels of metabolic hormones. While recent studies have examined the metabolic requirements of bone formation by osteoblasts, much less is known about the energetic requirements of bone resorption by osteoclasts. The abundance of mitochondria in mature osteoclasts suggests that the production of an acidified micro-environment conducive to the ionization of hydroxyapatite, secretion of matrix-degrading enzymes, and motility during resorption requires significant energetic capacity. To investigate the contribution of mitochondrial long chain fatty acid β-oxidation to osteoclast development, we disrupted the expression of carnitine palmitoyltransferase-2 (Cpt2) in myeloid-lineage cells. Fatty acid oxidation increases dramatically in bone marrow cultures stimulated with RANKL and M-CSF and microCT analysis revealed that the genetic inhibition of long chain fatty acid oxidation in osteoclasts significantly increases trabecular bone volume in female mice secondary to reduced osteoclast numbers. In line with these data, osteoclast precursors isolated from Cpt2 mutants exhibit reduced capacity to form large-multinucleated osteoclasts, which was not rescued by exogenous glucose or pyruvate, and signs of an energetic stress response. Together, our data demonstrate that mitochondrial long chain fatty acid oxidation by the osteoclast is required for normal bone resorption as its inhibition produces an intrinsic defect in osteoclast formation.

Keywords: CPT2; bone; glucose; lipid metabolism; osteoclast

DOI: https://doi.org/10.3389/fphys.2022.997358