Dataset Information

Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels.

ABSTRACT:

Objective

Aging is associated with compromised immune function and arterial remodeling and stiffness. The purpose of this study is to investigate whether in vivo AAV-based delivery of secreted Klotho (SKL) gene (AAV-SKL) improves aging- and senescence-associated immune dysfunction and arterial stiffness.

Methods and results

Senescence-accelerated mice prone strain 1 (SAMP1, 10 months) and old mice (20 months) were used. Serum SKL levels, B-cell population and serum IgG levels were markedly decreased in SAMP1 and old mice. Rescue of downregulation of serum SKL levels by in vivo AAV2-based delivery of SKL gene (AAV-SKL) increased B-cell population and serum IgG levels and attenuated arterial stiffness in SAMP1 and old mice. Thus, Klotho deficiency may play a role in senescence- and aging-associated humoral immune dysfunction and arterial stiffness. Vascular infiltration of inflammatory cells and expression of TGFβ1, collagen 1, scleraxis, MMP-2 and MMP-9 were increased while the elastin level was decreased in aortas of SAMP1 and old mice which can be rescued by AAV-SKL. Interestingly, treatment with IgG effectively rescued arterial inflammation and remodeling and attenuated arterial stiffness and hypertension in aging mice. In cultured B-lymphoblast cells, we further showed that SKL regulates B-cell proliferation and maturation partly via the NFkB pathway.

Conclusion

Aging-associated arterial stiffening may be largely attributed to downregulation of B-cell population and serum IgG levels. AAV-SKL attenuates arterial stiffness in aging mice partly via restoring B-cell population and serum IgG levels which attenuates aging-associated vascular inflammation and arterial remodeling.

SUBMITTER: Fan J

PROVIDER: S-EPMC10082671 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels.

Fan Jun J Wang Shirley S Chen Kai K Sun Zhongjie Z

Cellular and molecular life sciences : CMLS 20220824 9

<h4>Objective</h4>Aging is associated with compromised immune function and arterial remodeling and stiffness. The purpose of this study is to investigate whether in vivo AAV-based delivery of secreted Klotho (SKL) gene (AAV-SKL) improves aging- and senescence-associated immune dysfunction and arterial stiffness.<h4>Methods and results</h4>Senescence-accelerated mice prone strain 1 (SAMP1, 10 months) and old mice (20 months) were used. Serum SKL levels, B-cell population and serum IgG levels were ...[more]

PMID: 36001158

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Project description:BackgroundThroughout life, physiological homeostasis is challenged and the capacity to cope with such challenges declines with increasing age. In many species, sex differences exist in life expectancy. Sex-specific differences have been related to extrinsic factors like mate competition and/or intrinsic proximate mechanisms such as hormonal changes. In humans, an intrinsic factor related to aging is soluble alpha klotho (α-Kl). Both sexes show an age-related decline in α-Kl, but throughout life women have higher levels than men of the same age. Sex differences in α-Kl have been linked to a shorter lifespan, as well as to specific morbidity factors such as atherosclerosis and arteries calcifications. In non-human animals, information on α-Kl levels is rare and restricted to experimental work. Our cross-sectional study is the first on α-Kl levels in two long-lived species: bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). As in most mammals, female bonobos and chimpanzees have longer life expectancy than males.MethodsWe measured serum α-Kl levels of 140 subjects from 16 zoos with an ELISA to examine if α-Kl levels reflect this difference in life expectancy.ResultsIn both species and in both sexes, α-Kl levels declined with age suggesting that this marker has potential for aging studies beyond humans. We also found species-specific differences. Adult female bonobos had higher α-Kl levels than males, a difference that corresponds to the pattern found in humans. In chimpanzees, we found the opposite: males had higher α-Kl levels than females.ConclusionWe suggest that contrasting sex differences in adult α-Kl levels mirror the dominance relations between females and males of the two Pan species; and that this might be related to corresponding sex differences in their exposure to stress. In humans, higher cortisol levels were found to be related to lower α-Kl levels. We conclude that there is great potential for studying aging processes in hominoids, and perhaps also in other non-human primates, by measuring α-Kl levels. To better understand the causes for sex differences in this aging marker, consideration of behavioural parameters such as competition and stress exposure will be required as well as other physiological markers.

Project description:ObjectivesThe association between dietary carotenoid intake and Soluble Klotho (S-Klotho) levels among the elderly population requires further evaluation. The purpose of this study is to evaluate the relationship between the dietary carotenoid intake and the S-Klotho plasma levels in older adults.MethodsEligible participants aged 60 years or above were selected from the National Health and Nutrition Examination Surveys (NHANES) data, collected between 2007 and 2016. The consumption of carotenoids was determined through two 24-hour dietary recall assessments. Moreover, the S-Klotho levels in the serum were measured using an Enzyme-Linked Immuno-Sorbent Assay (ELISA).ResultsA total of 5,056 participants were included in the study having a median total carotenoid intake of 9775.25 μg (95% confidence interval (CI): 8971.30-10579.21) and a median S-Klotho concentration of 815.59 pg/mL (95% CI: 802.59-828.60). The multivariable regression analysis showed that a single standard deviation increase in total carotenoid intake was significantly associated with an 8.40 pg/mL increase in S-Klotho levels (95% CI: 0.48-16.31). When the carotenoids were divided into quartiles, participants in the third ((4963.5μg/day,11662.5μg/day]) and fourth quartiles ((11662.5μg/day,377178μg/day]) showed higher S-Klotho levels compared to those in the first quartile. Among carotenoid subtypes, increased intake of α-carotene, β-carotene, and lutein with zeaxanthin was associated with elevated S-Klotho levels. These observed associations between carotenoid subtypes and S-Klotho levels remained consistent across male participants, having a normal weight, and a moderate physical activity based on stratified analysis.ConclusionThe total carotenoid intake was positively related to plasma levels of S-Klotho in the elderly population, particularly for α-carotene, β-carotene, and lutein with zeaxanthin. However, further research is needed to confirm these findings and explore the underlying mechanisms behind this relationship.

Dataset Information

Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels.

Objective

Methods and results

Conclusion

Publications

Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels.

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