2 replies to this topic

[TianZi]

http://www.sciencece...ifespan-control

Being a resident of Taiwan, I recently came across this study by Taiwanese researchers.

[AgeVivo]

nice, but be careful to pretended "roles in aging":

CISD2-deficient knock-out mice (...) premature-ageing phenotype

there are many models of "premature-aging", that in fact do not allow to see how to extend lifespan.
Let's wait for CISD2-*overexpression* and associated lifespan...

The CISD2 gene is located on the long arm of human chromosome number 4, which has been previously implicated in the regulation of human longevity through a comparative genome analysis of centenarian siblings.

if i read correctly it says that the long arm of the chromosome has been associated with longevity, not the CISD2 gene...

Edited by AgeVivo, 26 May 2009 - 01:07 PM.

[Avatar of Horus]

Same topic:

Logan    Posted 15 April 2010 - 11:13 PM

http://www.scienceda...90514170758.htm

 

Role For CISD2 Gene In Human Disease And Lifespan Control
Date: May 14, 2009
Source: Cold Spring Harbor Laboratory
Summary:
A new animal model of human Wolfram Syndrome, and effectively link CISD2 gene function, mitochondrial integrity and aging in mammals.

 
It seems it has some role in normal aging too:
 

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice
Chen et al. Genes Dev. 2009
http://www.ncbi.nlm....pubmed/19451219
Abstract
CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. ...

Cisd2 mediates mitochondrial integrity and life span in mammals
Chen et al. 2009
http://www.ncbi.nlm....pubmed/19717971
Abstract
CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Using a mouse genetic approach, this work demonstrated for the first time that Cisd2 is involved in mammalian life span control. Cisd2 deficiency in mice leads to mitochondrial breakdown and dysfunction; this is accompanied by cell death with autophagic features and these events precede the two earliest manifestations of nerve and muscle degeneration. Together, they lead to a panel of phenotypic features suggestive of premature aging. This work effectively links Cisd2 gene function, mitochondrial integrity and aging in mammals.

A role for the CISD2 gene in lifespan control and human disease
Chen et al. 2010
http://www.ncbi.nlm....pubmed/20649540
Abstract
CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is an evolutionarily conserved novel gene. Recently, we have demonstrated that CISD2 is involved in mammalian lifespan control; this work also establishes WFS2 as a mitochondria-mediated disorder and effectively links CISD2 gene function, mitochondrial integrity, and aging in mammals. In wild-type mice, the expression levels of CISD2 decrease in an age-dependent manner during the naturally aging process; this correlates with mitochondrial breakdown and parallels the development of an aged phenotype. ...

A persistent level of Cisd2 extends healthy lifespan and delays aging in mice
Wu et al. 2012
http://www.ncbi.nlm....pubmed/22661501
Abstract
The CISD2 gene, which is an evolutionarily conserved novel gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Significantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Previously, we have shown that Cisd2 deficiency shortens lifespan resulting in premature aging in mice. Additionally, an age-dependent decrease in Cisd2 expression has been detected during normal aging. In this study, we demonstrate that a persistent level of Cisd2 achieved by transgenic expression in mice extends their median and maximum lifespan without any apparent deleterious side effects. Cisd2 also ameliorates age-associated degeneration of the skin, skeletal muscles and neurons. Moreover, Cisd2 protects mitochondria from age-associated damage and functional decline as well as attenuating the age-associated reduction in whole-body energy metabolism. These results suggest that Cisd2 is a fundamentally important regulator of lifespan and provide an experimental basis for exploring the candidacy of CISD2 in human longevity.

 
some details from the full text:
http://hmg.oxfordjou...21/18/3956.long

Since the beginning of time, humans have been searching for the secrets of the fountain of youth in order to promote longevity and help maintain quality of life in the old age. In addition to environmental factors such as nutrition control of diet and caloric restriction that can modulate lifespan, there is substantial evidence to support the familial aggregation of exceptional longevity in humans, which suggests that there is a genetic factor or factors associated with a long life. Thus, researchers have been wondering whether the fountain of youth has indeed a genetic component and does it stream from hundreds/thousands of genes, or only a very few?
...
Many genetic factors have the potential to modulate lifespan (9–13). However, so far, Cisd2 is the only identified gene that resides in the longevity region of 4q and has been demonstrated to be an essential gene for lifespan control by a loss-of-function mouse study. Nonetheless, experiments that shorten lifespan are likely to be less informative than those that prolong a healthy lifespan. Accordingly, it is very interesting and important to evaluate the life history of transgenic (TG) mice expressing an elevated level of the Cisd2 protein in order to see whether increased Cisd2 promotes longevity. In this study, we create a Cisd2 TG mouse model that is able to provide gain-of-function evidence, demonstrating that elevated expression of Cisd2, specifically a persistent level of Cisd2 during middle and old age, extends the healthy lifespan of mice and delays age-associated phenotypes in mice.

RESULTS
Cisd2 promotes longevity
To study whether enhanced expression of Cisd2 can extend lifespan, delay aging and help to retain the functional abilities lost with age, we generated Cisd2 TG mice carrying the Cisd2 coding region controlled by the RNA polymerase II large subunit (Pol II) promoter in a C57BL/6 mouse background (Fig. 1A). RNA analysis revealed a similar pattern for the endogenous and TG Cisd2 mRNA expression using northern blot hybridization (Fig. 1B). In wild-type (WT) mice, the levels of Cisd2 decrease in an age-dependent manner during aging (2). In the present study, we show that there is an average 38 and 57% decrease in the Cisd2 protein level in skeletal muscle of WT mice at middle age (12-month-old; 12-mo) and old age (24-mo), respectively, compared with young (3-mo) mice; however, in Cisd2 TG mice, there is a persistent expression level of the Cisd2 protein from young (3-mo) through middle age (12-mo) to old age (24-mo) (Fig. 1C). In the brain and skin, similar results were obtained for the age-dependent decrease in Cisd2 in the WT mice, whereas a persistent expression level of the Cisd2 protein in these tissues of the Cisd2 TG mice was observed as the mice aged.

An extended lifespan was evident for both sexes of the Cisd2 TG mice without any statistically significant sex differences (Table 1). In males (Fig. 1D, Table 1), the median lifespan of the Cisd2 TG mice was increased by 5.25 months (19.4%; from 27 months to 32.25 months) relative to WT mice (P < 0.001), whereas the maximum lifespan (mean lifespan of the oldest 10% within a cohort) was increased by 3.66 months (11.7%; P = 0.043). In females (Fig. 1E, Table 1), the median lifespan in Cisd2 TG mice was increased by 5.1 months (18.8%; from 27.15 to 32.25 months) relative to WT mice (P < 0.001), whereas the maximum lifespan was increased by 8.75 months (29.6%; P = 0.032).
...
Cisd2 delays skin aging
Age-associated structural and functional changes are more visibly evident in the skin than in any other organ in mammals. Interestingly, the fur of a very old (34-mo) Cisd2 TG mouse appeared to have less grey hairs (de-pigmentation) and to display a more prominent sheen than that of a middle-aged (15-mo) WT mouse (Fig. 2A). Histological examination (Fig. 2B–E) and quantification (Fig. 2F) revealed that age-dependent atrophy of the sebaceous glands, which are the lipid-producing structures associated with the hair follicles, was significantly delayed in Cisd2 TG mice at 24-mo. In addition, the proportion of individual hair follicles associated with two sebaceous glands was significantly increased in the Cisd2 TG mice at 24-mo (Fig. 2G).
... these results revealed that skin aging seems to be significantly delayed by the persistent expression of Cisd2 and, most obviously, Cisd2 alleviates sebaceous gland atrophy during skin aging.

Cisd2 delays muscle aging
Muscle strength declines with aging. Quantitative loss of muscle mass, namely sarcopenia, is the most important factor underlying this phenotype (20). Sarcopenia is accompanied by increased muscle fat infiltration, and the accumulation of fat mass in aged muscle has been shown to be a predictor of subsequent functional loss and disability in humans (21,22). Strikingly, constitutive Cisd2 expression has a profound effect and protects skeletal muscles from age-dependent mass losses and prevents fat infiltration (Fig. 3A–F). Quantification of the phenomena revealed that there was a significant increase in fiber size (Fig. 3G) and fiber number (Fig. 3H), as well as a significant decrease in lipid infiltration (Fig. 3I) in the Cisd2 TG mice at 24-mo. Furthermore, functional muscle strength improvement in the Cisd2 TG mice was demonstrated using a grip strength meter (Fig. 3J). A detailed transmission electron microscopy (TEM) examination further revealed that Cisd2 indeed protects from age-associated degeneration the mitochondria within and the ultrastructure of skeletal muscle, in Cisd2 TG mice, including myofilaments; this is in contrast to the overt mitochondrial degeneration, which is accompanied with autophagy, in the aged muscles of WT mice at 24-mo (Fig. 3K–N).

Cisd2 delays neuron aging
... Notably, considerable age-associated degeneration of the non-myelinated and myelinated axons as well as the disintegration of the myelin sheath were detected in the sciatic nerve (Fig. 4A and B) and optic nerve (Fig. 4C and D) of aged WT mice at 24-mo. Interestingly, the persistent expression of Cisd2 appears to protect the TG mice from the age-associated damage to both the sciatic (Fig. 4E and F) and optic nerves (Fig. 4G and H). Furthermore, neuron degeneration in the aged WT mice seems, in turn, to lead to a decrease in neuron density, which is supported by our quantification. Our results show that there are striking differences in the numbers of myelinated axons in the sciatic and optic nerves when WT and Cisd2 TG mice are compared, which suggest that Cisd2 appears to protect these nerves (Fig. 4I–L). To examine motor functions in older mice, we assessed behavior using an open-field locomotion test and rotarod trials. There was a trend toward better motor function in the Cisd2 TG mice compared with the age- and sex-matched WT mice at 24-mo (Supplementary Material, Fig. S4).

Cisd2 protects mitochondria from age-associated damage, reduces the age-associated declines in mitochondrial function and whole-body energy metabolism

Since Cisd2 deficiency causes mitochondrial dysfunction and triggers an accelerated aging process in Cisd2 KO mice, we sought to investigate whether an elevated level of the Cisd2 protein was able to protect mitochondria from age-associated damage in Cisd2 TG mice. There is progressive damage to mitochondrial DNA (mtDNA) during aging. To study whether Cisd2 is able to protect mitochondria from age-associated genomic damage, we examined mtDNA integrity by long polymerase chain reaction (PCR; 13.6 kb) of mtDNA (23) ...
Indeed, we detected a reduction in the amplification of the 13.6-kb fragment and an increase in the number of shorter PCR fragments in the old (24-mo) WT mice compared with the young (3-mo) mice (Fig. 5B and C). In contrast, the old (24-mo) Cisd2 TG mice were protected from this age-associated increase in mtDNA damage (Fig. 5B and C).

To investigate whether an attenuation of the age-associated damage to mtDNA has a direct functional benefit, we assessed aerobic respiration using isolated mitochondria prepared from skeletal muscle. Our results revealed an age-dependent decrease in oxygen consumption in both the WT and Cisd2 TG mice; however, there was a remarkable increase in the oxygen consumption of the mitochondria from the Cisd2 TG mice compared with those from the WT controls at the old age (24-mo) (Fig. 5F). ...
Together, these results show that constitutive expression of Cisd2 protects mitochondria and reduces the age-associated decline in aerobic respiration during aging.

To assess the impact of better preserved mitochondrial function on age-associated changes in whole-body energy metabolism, we monitored the mice by indirect calorimetry. Consistent with the decreased oxygen consumption observed using the isolated mitochondria of old (24-mo) WT mice, whole-body oxygen consumption (VO2), CO2 production (VCO2) and heat generation were significantly decreased in the old (24-mo) WT mice compared with the young (3-mo) WT mice during both light and dark cycles (Fig. 6A–F). In contrast, old (24-mo) Cisd2 TG mice were well protected from these age-associated reductions in O2 consumption, CO2 production and heat generation during the light cycle; furthermore, during the dark cycle, although the reduction in these age-associated parameters was not fully protected, the decline was significantly attenuated in the Cisd2 TG mice (Fig. 6D–F). Taken together, these results demonstrate that aging is associated with mitochondrial damage and is accompanied by a reduction in mitochondrial function and whole-body energy metabolism. Importantly, these deleterious changes can be prevented or significantly ameliorated by a persistent level of Cisd2 expression during aging.
...