|Abstract:||Gene silencing via RNA interference is mediated by microRNAs which are major controller of developmental processes and its plasticity conferred by diet. The function of specific miRNAs is going beyond the developmental period and extends in the control of lifespan via regulating the onset and the rate of aging.|
Non-coding RNAs (ncRNA) do not encode a protein gene product but functional RNA. ncRNA can be very long or extremely short. Among the former which are less then 200 nucleotides long are microRNA, short interfering RNA (siRNA), Piwi-interacting RNAs (piRNAs) and small nucleolar RNAs (snoRNAs).
MicroRNAs (miRNAs) are endogenous non-coding RNAs that regulate gene expression through translation modulation, RNA degradation or induction of heterochromatin. miRNA can mediate either repression  or induction [18498749; 18048652] of translation depending on the context of the miRNA binding site. Silencing occurs via near-perfect or partially complementary to target mRNA. The miRNA seed sequence comprise 2-7 bases and is important for recognition.
miRNA regulate developmental timing, neuronal asymmetry, germline cell division, reprogramming to induced pluripotent stem cells, p53-induced cell senescence and cancer progression. miRNAs act in regulatory pathways that extend and reduce lifespan. Heterochronic development circuit miRNAs lin-4 and lin-14 for example regulate longevity post-developmentally. miRNAs that change with age in C. elegans, mice and humans were identified by microarrays and RNA sequencing. miRNA expression in general declines with aging but in some tissues it appears to be the opposite. Some groups of the small RNAs exhibit particular large expression changes and some are consistently up or downregulated with age. For instance, let-7 is associated with larval development and cancer had the greatest decrease with age. Many of the age-regulated miRNAs are expressed primarily in the intestine, neurons, and somatic gonad, all tissues associated with regulation of aging.
Small non-coding RNAs (ncRNAs) compromise classes such as endogenous small inhibitory RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), QDE1-interacting RNAs (qiRNAs) and microRNAs (miRNAs). Some ncRNAs have not yet been identified in mammals and are dependent on RNA-dependent RNA polymerases. The mammalian enzyme consists of hTERT together with RMPR, an alternative RNA component. miRNAs are regulated during cellular senescence. miRNAs contribute to tissue regeneration by regulation of stem cell function. At least one miRNA modules C. elegans lifespan. miRNAs act as inhibitors of proteins mediating the insulin/IGF1 and TOR signaling .
miRNA regulate developmental decisions in C. elegans and are well conserved in plants and animals. miRNAs play an important role in regulating embryonic development also in vertebrates [He et al., 2011]. Specific non-coding RNA (ncRNA) circuitry mediates brain development, plasticity, stress response as well as aging [Qureshi and Mehler, 2011]. Developmental progression is coordinated epigenetically and affects the proliferation status of cells. For instance, mir-34b/c are able to modulate CpG methylation (differentiation) and interact with p53 signaling (cell proliferation control). microRNAs are mediators of life history changes which determine whether an animal ages or stays in a non-aging state .
Adult-specific knockdown of the C. elegans argonaute-like gene 1 alg-1 results in shortened lifespan. Similar observations were made in fruit fly. In Drosophila the endo-siRNA pathway regulates metabolism, defence against stress and aging. Dicer-2 (Dcr-2) loss changes the expression of mostly metabolic genes implicated in stress resistance and aging. Dcr-2 mutants had reduced lifespan and were hypersensitive to oxidative, endoplasmic reticulum, starvation and cold stresses as well as abnormal lipid and carbohydrate metabolism [Lim et al., 2011].
In C. elegans miRNA lin-4 and its target gene lin-14, which encodes a transcription factor, control larval developmental timing. Overexpression of lin-4 miRNA or suppression of lin-14 extends lifespan [Boehm and Slack, 2005]. In line with this, lin-4 loss-of-function mutation or lin-14 gain-of-function mutant (lacks lin-4 binding site) leads to decreased lifespan. Knockdown of lin-14 only during adulthood is sufficient to extend lifespan and suppresses the short lifespan phenotype of lin-4 mutants. lin-4 mutants display an increased rate of aging, while lin-14 mutants exhibit retarded aging. Lifespan extension conferred by lin-14 reduction is mediated by DAF-16 and HSF-1. lin-4 is itself regulated by DAF-16 in L1 arrest.
Specific miRNA in C. elegans can promote or antagonize aging. While mutating miR-71, miR-238 and miR-246 decreases lifespan, the overexpression of miR-71 or miR-246 increase lifespan. Whereas miR-239 mutants have a shortened lifespan, overexpression of miR-239 blesses the animal with extended longevity. Lifespan extension by mir-239 loss-of-function requires daf-16 [de Lencastre et al., 2010].
mir-58(n4640), miR-61 mir-250(nDf59), mir-64-66 mir229(nDf63), miR-71(mir-71(n4115), mir-80 mir-227(nDf53; mir81-82(nDf54) and mir-238 significantly shorten the lifespan if knocked down [Boulias et al. 2012] (at 20 degree Celsius; maybe also miR-49).
In Drosophila mutating miR-14 (which is a cell death suppressor) reduces lifespan [Xu et al., 2003].
Specific miRNAs are altered in expression during aging [de Lencastre et al., 2010; Ibanez-Ventoso and Driscoll, 2009; Kato et al., 2011].
In C. elegans more than 34 miRNAs exhibit changes in expression during adulthood (31 > two-fold) [Ibanez-Ventoso et al., 2006]. In whole body of worms there is an overall decline in miRNA expression [de Lencastre et al., 2010; Ibanez-Ventoso and Driscoll, 2009; Ibanez-Ventoso et al., 2006]. Expression patterns of developmental timing regulators lin-4 and let-7 miRNAs as well as conserved muscle miRNA miR-1 are regulated also during the adulthood [Ibanez-Ventoso et al., 2006]. In whole body of worms there is an overall decline in miRNA expression [de Lencastre et al., 2010; Ibanez-Ventoso and Driscoll, 2009].
Similar in mammals the majority of miRNA decrease in abundance with aging in brain and peripheral blood monocular cells [Noren Hooten et al., 2010; Persengiev et al., 2011]. However, in specific somatic tissues such as liver there were more upregulated than downregulated miRNAs during aging [Li et al., 2011a; Maes et al., 2008].
In livers of aged mice (4 vs. 33 month) four miRNA (miR-93, miR-669c, miR-214 and miR-709) were especially upregulated and correlated with the protein expression of their target genes which are associated to mitochondrial function, oxidative stress and proliferation [Maes et al., 2008]. miR-669c and miR-709 levels increase during mid-age (18 to 33 month) in murine liver. miR-93 and miR-214 are higher in extreme old (33 vs. 4 or 10 month) mice [Maes et al., 2008]. miR-93, miR-214 and miR669c all target detoxification and regeneration genes which decline in activity with age [Maes et al., 2008]. miR93, miR-214 and miR-709 increase with age and target UQCRC1 (a component of the cytochrome c complex) which also declines in older liver. miR-34a and miR-93 expression increase with age and target MGST1 and SIRT1 as well as SP1 and NRF2 (both are transcription factors targeting MGST1 and SIRT1), which are all becoming downregulated during aging [Li et al., 2011b].
About 70 miRNAs are upregulated during mid-adulthood (18 month) in murine brain. Some of them are exactly the same which are also upregulated in liver [Li et al., 2011a]. Specifically upregulated in brain were miR-22, miR-101a, miR-720 and miR-721 [Li et al., 2011a]. 27 of the 70 miRNAs have predicted target gene encoding components of the mitochondrial transport chain and F1F0-ATPase, which decrease which aging and therefore explaining the decreased respiration rates occurring during aging [Li et al., 2011a].
Aging in murine muscle leads to differentially expression of at least 67 miRNA including miR-221 which regulates myogenic precursor [Hamrick et al., 2010]. miR-7, miR-468, miR-542 and miR-698 were most substantially increased, while miR-124a, miR-181a, miR-221, miR-382, miR-434 and miR-455 levels were most strongly decreased. Treatment with the hunger hormone leptin reversed a considerable number of these changes. Also in humans at least 18 miRNAs are differentially expressed during muscle aging (31 vs. 73 years). let-7b and let-7e are increased in expression in skeletal muscle during human aging. These let-7 family members repress cell cycle regulators CDK6, CDK25A and CDC34 as well as PAX7, crucial for satellite cell turnover [Drummond et al., 2011].
pri-miRNA-1-1, -1-2, 133a-1 and -133a-2 expression were elevated in skeletal muscle of older humans [Drummond et al., 2008].
Numerous miRNAs are commonly downregulated and a few are commonly upregulated during aging in the cortex and cerebellum of humans, chimpanzees and macaques. For instance, among those is miR-144 that targets ataxin-1 which is also increase in all three species during aging [Persengiev et al., 2011].
In human peripheral blood mononuclear at least 9 miRNA (miR-103, miR-107, miR-128, miR-130a, miR-155, miR-24, miR-221, miR-496 and miR-1538) were lower in older individuals. Their predicted target genes such as PI3K, c-Kit and H2AX are elevated with advanced age. Decreasing expression of miR-221 was sufficient to cause increase in its target gene PI3K which in nematodes if knockout extends lifespan by ten-fold.
Peripheral blood of adult woman (22 - 25 vs. 36 - 39 years) exhibits significantly distinct patterns of miRNAs, but mRNA gene expression. However there exists a weak global correlation between these two types of expression levels. Most differentially expressed miRNAs include miR-155, -18a, -142, -340, -363, -195, and -24 and there target genes are enriched for estrogen regulation [Sredni et al., 2011].
Deep sequencing identified miRNAs that change with age (young; day 0 of adulthood vs. middle-aged; day 10) in wild-type and long-lived daf-2 mutants. 11 were new miRNAs, several of which share homology with miRNAs in higher eukaryotes.
Although in general it appears the miRNA expression gradually declines with aging, some miRNA increase with age in expression levels, such as miR-144 in chimpanzees and humans as well as let-7 and miR-34a in mouse [Inukai et al. 2012; Persengiev et al. 2011; Li et al. 2011].
miR-145 and miR-375 decline in mouse brain during aging and have target genes involved in insulin signaling [Noren Hooten et al. 2012; Inukai et al. 2012].
Declining miRNAs in human blood are associated with the loss of repression of cancer-associated genes as they target p53 signaling, citrat cycle and other cancer-related processes [Elsharawy et al. 2012].
Decline in cellular health status occurs at mid-life. This decline may involve a universal or system-specific programmatic shift of signaling control [Wang, 2007].
Some of the miRNAs upregulated with age regulate longevity. Three miRNAs with large expression increases with age affected lifespan. miR-239 that increased longevity (i.e. positive gerontogene) and stress resistance, while its overexpression shortens lifespan (negative gerontogene). miR-71 and miR-246 mutants had decreased lifespan, while overexpression increased lifespan (positive and negative ageing-suppressors). miR-239 and miR-71 likely function in IIS (insulin/insulin-like growth factor signaling), because miR-239-mediated effects on longevity are daf-16-dependent and loss of daf-16 does not further shorten miR-71’s lifespan. pdk-1 (IIS) and cdc-25.1 (cell cycle checkpoint) had predicted miRNA-binding sites in their 3’UTR and their expression is altered in the miR-71 mutant, thus function as a link between IIS and DNA-damage checkpoint longevity pathways [de Lencastre et al., 2010]. The miRNA mutants did not appear to have obvious changes in developmental rates, reproductive timing, or progeny production, while longevity regulators like daf-2, eat-2 and mitochondrial mutants had obvious developmental phenotypes. miR-71 is upregulated during starvation, induced by diapause and during post-dauer recovery as well as during starvation-induced early dormancy [Karp et al., 2011]. Both miR-71 and miR-238 are upregulated during starvation-induced early dormancy. miR-71 is actually required for dauer recovery by suppressing certain heterochronic genes [Zhang et al., 2011].
Polycomb group (PcG) proteins like BMI1 control stem cell aging through regulation of aging-related genes such as the p16INKa/p19ARF locus, by triggering an increase in repressive histone marks (e.g. H3K27me3) [Bracken et al., 2007]. PcG proteins BMI1 and EZH2 are regulated by DNA-methyltransferases in a mechanism dependent on specific miRNA expression [So et al., 2011].
Senescence is an irreversible growth arrest program of cells, which can be induced by telomere attrition, oxidative stress, oncogene expression, or DNA damage signaling.
The establishment of senescence is associated with specific gene expression changes in p16, p53, and p21 , chromatin silencing of E2F target genes  and protein phosphorylation by DNA damage checkpoint kinases .
Senescence-associated miRNAs regulate genes related cell cycle, cytoskeletal remodelling and proliferation signaling. Different senescence-induction mechanisms regulate a common set of processes .
mir-34 family, particularly miR-34a, as downstream effectors of p53 involved in cell cycle , leads to cell cycle arrest, increased expression of Beta-galactosidase  and downregulation of E3F family target genes . MDM2 inhibiting drug Nutlin-3, leads to p53 activation, induced up-regulation of primarily miR-34a and later miR-3b and miR-34c .
Overexpression of hsa-miR-20a in mouse embryonic fibroblasts induces senescence by lowering LRF 9a transcriptional repressor of the MDM2 inhibitor p19ARF [15662416; 9529248] protein levels and in turn increasing p19ARF levels .
hsa-miR-371, hsa-miR-369-5p, hsa-miR-29c, hsa-miR-499 and hsa-let-7f are significantly upregulated in senescent human mesenchymal stem cells (hMSCs) when compared to early passage hMSC . has-miR-217 is also significantly upregulated but overall had very low expression levels.
miR-372 and miR-373 expression is able to bypass RAS-induced senescence in presence of wild-type p53 .
Upregulation of miR-143 is linked to senescence-dependent growth arrest in human fibroblasts [Bonifacio and Jarstfer, 2010].
Expression of senescence-related miRNAs, including let-7 family, miR-23a, miR-26a and miR-30a might be regulated by the activity of HDACs (Histone deacetylase complexes) [Lee et al., 2011].
miR-17, miR19b and miR-20a are downregulated during aging and/or senescence. Their decreased expression correlated with the increased transcript levels of their target genes, such as CDKN1A (p21) [Hackl et al., 2010].
miR-29 and miR-30 miRNA families are upregulated during induced and replicative senescence. Their upregulation requires the Rb pathway. B-Myb oncogene is repressed by miR-29 and miR-30. Interference with miR-29 and miR-30 expression inhibits senescence [Martinez et al., 2011].
miR-203 regulates p63 as well as Cav-1 and is involved in differentiation of skin stem cells [Lena et al. 2008; Yi et al. 2008]. Cav-1 is involved in cholesterol homeostasis, vesicular transport and signal transduction regulation [Williams et al. 2006]. miR-203 target sites in both Cav-1 and p63 3’UTRs exhibit high conservation across a number of species. Both p63 and Cav-1 are repressed by DR via miR-203.
A cohort of miRNA including miR-138, -181a, -181b and -130b increased in expression with serial passages, miR-138m -181a an -181b, but not miR-130b overexpression was sufficient to induce senescence. Sirt1 is a direct target of miR-138m -181a and -181b, whereas ΔNp63 expression was inhibited by miR-130b. ΔNp63 inhibits miR-138, -181a, -181b and -130b expression by binding directly to p63-responsive elements located in close proximity. Changes in miRNA expression by modulating the levels of regulatory proteins like p63 and Sirt1 strongly contributes to induction of senescence [Cervo et al., 2012].
Senescent cells secrete various kinds of inflammatory cytokines such as IL-6 and IL-8, as part of the senescence associated secretory phenotype which induces a bystander effect and leads to malignancy. miR-146a/b is significantly elevated during senescence as a compensatory response to restrain inflammation via the suppression of IL-6 and IL-8 secretion and downregulation of IRAK1 (component of IL-1 receptor signaling). IL-1α neutralizing antibodies abolish both miR-146a/b expression as well as IL-6 secretion [Bhaumik et al., 2009].
miR-19 reduces PTEN levels and thus activates AKT/MTOR pathway. miR-19 and other members of the miR-17-92 cluster are commonly downregulated in several human replicative and organismal ageing models [Grillari et al., 2010].
LMNA mutation results in Hutchinson-Gilford Progeria Syndrome (HGPS). Zmpste24-deficient mice which age prematurely (a murine model of HGPS) have deregulated miR-29 expression [Ugalde et al., 2011]. miR-29 is also upregulated in somatic tissues from normal old mice. Its increased expression is strongly associated with DNA damage and p53-pathway [Ugalde et al., 2011]. These mice have also higher levels of miR-1 (targets IGF1) in liver, kidney as well as muscle.
Werner Syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. miR-124 expression is lost in the liver of Wrn helicase mutant mice. The expression of the conserved miR-124 in whole wrn-1 mutant worms is also reduced. Loss of mir-124 in nematode increases reactive oxygen species formation and accumulation of aging marker lipofuscin, reduces whole body ATP levels and results in a reduction in lifespan. Supplementation of vitamin C normalizes the median lifespan of wrn-1 and mir-124 mutants .
Mice deficient in klotho age prematurely. miR-29 members are upregulated in klotho-deficient mice and also in normally elderly ICR mice relative to wild-type littermates and young ICR mice. Levels of type IV collagen, a major component of basement membranes and a putative target of miR-29 are lower in klotho(-/-) and elderly ICR mice than in wild-type and littermates and young ICR-mice .
Diet restriction (DR) extends the lifespan in all biomedical tested model organisms. Strikingly under DR there is instead of an age-dependent decrease in miRNA expression an age-dependent increase in brain miR-34a, miR30e and miR181-a-1, which target Bcl2, CREB1 and HTT [Khanna et al., 2011]. DR and exercise induce neurotropic factors (including BDNF), cytoprotective, chaperons and anti-apoptotic proteins. Neuroprotective effectors of DR and exercise are mediated, in part, by gene transcription changes . The beneficial effects of DR on the aging brain may be due to down-regulation of miRNAs that target mRNAs encoding cell survival proteins . Levels of the three miRNAs (miR-34a, miR30e and miR181-a-1) are lower in brain tissue samples form old mice (24 - 28 months) maintained on DR (40% beginning at 4 months). All three miRNAs have at least one target site for Bcl2, anti-apoptotic protein, which increase with DR. Overexpression of miR-30a, miR-34a and miR-181a result in decreased BCL2 levels and increased apoptosis via increases in pro-apoptosis genes such as Bac and cleavage of Caspases. miRNA expression change occurred in both cortical and hippocampal tissues, indicating a more global repression of these miRNAs in the central nervous system (CNS) due to DR. Additional shared targets were cAMP response element binding protein 1 (CREB1), important activator of several immediate response genes that are critical to synaptic plasticity [Deisseroth et al. 2003] and Huntington (HTT). miR-30a has an identical seed region to miR-30e acts to functionally repress BDNF expression in cortex [Mellios et al. 2008]. BDNF upregulation by DR mediates, in part, the increased neurogenesis by DR and is important in learning and memory [Lee et al. 2002; Mattson et al. 2004].
DR induces expression of miR-29c, miR-203, miR-150 and miR-30 in breast tissue of mice. miR-29 and miR-30 are involved in senescence [Martinez et al. 2011].
It has been found that miR-203 is induced to great proportion by way of restricting calories. It has been demonstrated that caveolin-1 and p63 are direct targets of miR-203 in vivo during restriction of calories. Moreover, this kind of regulatory action has implications in both mouse models as well as humans as demonstrated by cell culture studies [Ørom et al. 2012].
In a recent study, detailed analyses were performed on circulating serum miRNAs in three mouse model types (young mice, old mice, and old mice on dietary restriction). It was found that serum levels of certain miRNAs increased with age. Moreover, dietary restriction seemed to counteract this increase [Dhahbi et al. 2013].
miR-34a target genes are highly enriched for growth factor signaling and cell cycle progression which form a dense network that orchestrate the proliferative response to external growth stimuli.
mir-34 mutation extends lifespan by enhancing autophagic flux in C. elegans and mir-34 represses autophagy by inhibiting Atg9 in mammalian cells. mir-34 loss of function mutation in C. elegans delays age-related physiological decline, extends lifespan, and increases resistance to heat and oxidative stress. RNAi against autophagy-related genes, atg4, bec-1 or atg9 reversed lifespan extending effect of mir-34 mutants. miR-34a inhibits Atg9A expression post-transcriptional [Yang et al., 2011].
miR-34 regulates age-associated events and long-term brain integrity in Drosophila. miR-34 expression begins in the adulthood, is enriched in brain and increase with age. mir-34 loss triggers a gene expression profile of accelerated brain aging, late-onset brain degeneration and catastrophic decline in survival, while mir-34 upregulation extends median lifespan and mitigated neurodegeneration induced by polyglutamine. mir-34 silences Eip74EF (ETS domain transcription factor involved in steroid hormone pathways). miRNAs silence antagonistic pleiotropic developmental genes. Most miRNAs maintain a steady state level or decrease with gene, but not mir-34 which increases. It is barely detectable during development, but becomes high in adulthood and only its isoform c becomes upregulated with age. miR-34 mutants have no obvious developmental defects. miR-34 binding sites within the 3’UTR of the Eip74EF gene are conserved in orthologous Eip74EF genes from different Drosophila species. Eip74EF is a component of the steroid hormone signalling pathways which was studied primarily during development but was also implicated in lifespan regulation [Simon et al. 2003]. Flies lacking miR-34 had markedly increased E74A protein levels. E74A protein is highly expressed in young flies, but underwent a marked decrease within a 24h time window, which is mutually exclusive to the expression of miR-34. In flies lacking miR-34, the downregulation of E74A protein during the critical period was dampened. Deregulated expression of E74A has a negative impact on normal aging. One function of miR-34 is therefore to silence E74A in the adult to prevent the adult-stage deleterious activity of E74A on brain integrity and viability.
mir-34 expression is elevated with age in C. elegans too [de Lecanstre et al. 2010; Ibanez-Ventoso et al 2006]. Mammalian mir-34 orthologous are highly expressed in adult brain [Bak et al. 2008], increase with age and misregulated in degenerative diseases in humans [Zovoilis et al. 2011; Minones-Moyano et al 2011; Khanna et al. 2011; Gaughwin et al. 2011]. miR-34 function is neutral or adverse in C. elegans [de Lencastre et al. 2010, Yang et al. 2011] and can be either protective or contributory to age-associated events in vertebrates [Zovoilis et al. 2011; Minones-Moyano et al 2011; Khanna et al. 2011; Gaughwin et al. 2011].
Ames dwarf mice, which are long lived due to deficiency in pituitary hormones, have increased expression of ten miRNAs, including miR-27a. miR-27a post-transcriptionally suppresses key proteins of intermediate metabolism (glutathione metabolism, the urea cycle and polyamine biosynthesis), notable the biosynthetic pathway involving ornithine decarboxylase and spermidine synthase. The repressive action of miRNA-27a on ornithine decarboxylase in dwarf mouse liver was found as early as 2 months of age [Bates et al., 2010].
Various miRNAs are upregulated in the hippocampus of both long-lived Ames dwarf mice and growth hormone-receptor-knockout mice [Liang et al., 2011]. miR-470, miR-669b and miR-681 suppress expression of IGF1R and AKT (as well as its phosphorylation) which results in decreased FOXO3 phosphorylation (hence activation).
The expression patterns of just few miRNAs in C. elegans are predictive for the longevity of an individual and capable to predict up to 47% lifespan differences. mir-71 and mir-246 correlate with lifespan, while mir-239 anti-correlates and act upstream of insulin/IGF-1 like signalling (IIS) and other longevity pathways [Pincus et al., 2011].
In mice blood circulating miR-34a levels start to raise as early as 4 months, just before tissue deterioration begins and correlates with downregulation of its target gene SIRT1 in the blood as well as brain [Li et al., 2011c].
In mice and humans, miRNA levels measured in peripheral blood mononuclear cells correlate with aging [Noren Hooten et al., 2010] and even a single miRNA can function as marker for brain aging, neurodegeneration and memory impairment [Zovoilis et al., 2011].
16 miRNAs are up-regulate and 64 down-regulated in long-lived individuals [Elsharawy et al., 2012].
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