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Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

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Review

Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

Sára Sándor et al. Front Genet.

Abstract

Aging research has experienced a burst of scientific efforts in the last decades as the growing ratio of elderly people has begun to pose an increased burden on the healthcare and pension systems of developed countries. Although many breakthroughs have been reported in understanding the cellular mechanisms of aging, the intrinsic and extrinsic factors that contribute to senescence on higher biological levels are still barely understood. The dog, Canis familiaris, has already served as a valuable model of human physiology and disease. The possible role the dog could play in aging research is still an open question, although utilization of dogs may hold great promises as they naturally develop age-related cognitive decline, with behavioral and histological characteristics very similar to those of humans. In this regard, family dogs may possess unmatched potentials as models for investigations on the complex interactions between environmental, behavioral, and genetic factors that determine the course of aging. In this review, we summarize the known genetic pathways in aging and their relevance in dogs, putting emphasis on the yet barely described nature of certain aging pathways in canines. Reasons for highlighting the dog as a future aging and gerontology model are also discussed, ranging from its unique evolutionary path shared with humans, its social skills, and the fact that family dogs live together with their owners, and are being exposed to the same environmental effects.

Keywords: aging genetics; animal aging models; dementia research; family dogs; hallmarks of aging.

Figures

Figure 1
Figure 1
Main mechanisms of aging.The figure depicts the mechanism that underlie cellular aging and, consequently, aging of a multicellular organism. The main mechanisms defined as hallmarks of aging by López-Otín et al. in 2013 are numbered according to their order in the main text. (A) The DNA repair machinery provides the first line of defence against mutagenic agents and also interacts with mobile DNA elements through repairing double strand breaks induced by transposons. Impaired function of this machinery can be a main contributor to Genomic instability (1). (B) Reactive oxygen species produced by mitochondrial respiration represent an inner source for DNA lesions, thus interact with the DNA repair machinery: proper functionality of DNA repair enzymes is required to protect cells from oxidative damage, however elevation in the level of oxidative stress may overburden the repair machinery. Age-related Mitochondrial dysfunction (6) can lead to increased oxidative and apoptotic burden. In addition, increased oxidative stress can also affect proteostasis. (C) Macroautophagy is a protective mechanism against malfunctioning mitochondria that might cause oxidative stress, while together with other clearance mechanisms it also functions to remove misfolded proteins and protein aggregates. It also functions as a mechanism for programmed cell death (indicated with dashed line between autophagy and cell cycle control). Together with the ubiquitin-proteasome system (not indicated separately on the figure) its malfunction may lead to Loss of proteostasis (4) in cells. (D) The activity of the autophagy machinery is strictly regulated by different signalling pathways, many of which function in metabolite sensing and cell growth control. Dysruption in these signaling pathways is summarized as Deregeulated nutrient sensing (5) by López-Otín et al (2013). (E) Cell cycle control is a main determinant of Cellular senescence (7). Also, on a multicellular level, dysregulation of cell cycle control may decrease lifespan by initiating tumour formation. (F) In many species telomeres function as a measuring mechanisms to limit the number of potential cell cycles. When telomere length reaches a critical shortness, it will activate cell cycle control mechanisms to render the cell into a senescent state. The telomerase enzyme was also shown to interact with global genomic chromatin maintenance. In general, Telomere attrition (2) is a main hallmark of aging in most mammalian species. (G) Epigenetic regulation involves two main mechanisms, the methylation of CpG islands and modification of the chromatin structure through histone proteins. Chromatin structure at telomeres is important for telomere maintenance and the repression of retroelements by CpG methylation may prevent DNA damage caused by transposon mobilisation. Epigenetic alterations (3) are also linked to aging in both humans and model organisms. (H) Derepression of mobile DNA elements, primarily of retroelements in mammalian genomes, may result in an increased frequency of double strand breaks and insertion mutagenesis leading to increased Genomic instability (1). (I) Altogether, the molecular mechanisms of aging eventually result in Cellular senescence (7). (J) Cellular senescence will lead to reduced function of tissues in a multicellular organism. Depletion of tissue renewing stem cells (8) is also a main hallmark of organismal aging and is a result of cellular senescence and increased activation / differentiation of dormant stem cells in certain tissues. (K) Loss of stem cells and cellular senescene will lead to functional decline in the central nervous system. (L) Altered intercellular communication (9) is also considered a main hallmark of aging in multicellular organisms, as coordinated activity of cells is essential for proper tissue functionality. (M) The immune system can be affected considerably by altered intercellular communication, and this could also lead to increased inflammation in the body, called inflamm-aging. The elevated levels of inflammation may also result from the increasing number of senescent / apoptotic cells. (N) Together with intracellular changes, mainly loss of genomic integrity, disrupted proteostasis and signalling pathways, the imbalanced function of the immune system will contribute to the occurrence of age-related diseases.
Figure 2
Figure 2
The protective roles of the DNA repair machinery. The DNA repair machinery counteracts the effects of variable DNA damaging processes. In healthy cells, the repair machinery can balance these deleterious effects (represented by red arrows); however, in the case of increased mutagenic burden (e.g., exposure to UV radiation), or when members of the repair machinery are not functioning properly, the balance can be lost and a growing number of DNA lesions may cause the cells to die or turn malignant. (A) The function of the Mismatch Repair system (MMR) is coupled to DNA replication where mismatching base pairs can be formed spontaneously and are being identified and repaired by MMR proteins. (B) The Base Excision Repair (BER) system can detect damaged/chemically modified bases in the DNA helix, and remove them, resulting in an apurinated site, which will induce endonucleases to cut back the DNA strand. The single strand break is repaired by a DNA polymerase based on the sequence of the complementary strand, and the newly synthesized sequence is ligated to the original DNA strand by a ligase enzyme. (C) Mutations that disrupt the normal topology of the DNA double helix, like the UV-light induced formation of pyrimidine dimers, are corrected by the nucleotide excision repair (NER) system. This machinery recognizes aberrant DNA structure caused by chemically modified nucleotides and removes these nucleotides resulting in a single strand break, which will be filled in by DNA polymerase and ligase enzymes. (D, E) The most destructive form of DNA damage is double strand break (DSB), which could trigger an immediate apoptotic response if it fails to be repaired. Two distinct mechanisms are used by cells to repair DSB: one is homologous recombination (HR) and the other is non-homologous end joining (NHEJ). HR is a fundamental process also linked to meiosis in eukaryotic cells, and it provides a possibility to recover the damaged DNA strand in full length, by using a homologous DNA helix (e.g., the sister chromatid) as template. In contrast, NHEJ may link ends of double stranded DNA together randomly, which could lead to loss of sequences around the breakpoint. All types of DNA repair are indispensable for normal cellular and organismal function.
Figure 3
Figure 3
Mobilization of retroelements in the genome. This picture shows the basic mechanism of retrotransposon mobilization. (A) Normally, activity of functional retroelements, like LINE-1, is repressed in somatic cells by methylation of CpG islands in their promoter regions. (B) Demethylation of the transposon promoter may result in transcriptional activation. The transcribed mRNA encodes the proteins necessary for retrotransposition, the Integrase (Int) and Reverse Transcriptase (RT), and also serves as template for reverse transcription. The reverse transcribed transposon DNA will be integrated into the genome by the Int protein, which first induces a double strand break. (C) The retroelement has copied itself into a new genomic region.
Figure 4
Figure 4
The role of telomeres and epigenetics in chromosomal integrity and aging. The figure illustrates how shortening of telomeres and changes in the epigenetic pattern affect the overall structure of chromosomes. (A) Chromosome ends are protected by repetitive sequences called telomeres in most eukaryotic organisms. This telomere sequence, consisting of TTAGGG repeats, shortens with each DNA replication, which eventually triggers cellular senescence. (B) Chromatin changes occur on the first level of DNA packaging, when the DNA double strand is coiled up on nucleosomes. Tight coiling on nucleosomes results in a heterochromatic state, when the DNA double helix is not accessible to many proteins, including the transcription machinery. In contrast, reduction in the number of nucleosomes leads to a less coiled and less dense state rendering the DNA more open to transcription. (C) DNA methylation at CpG islands cause chemical changes directly in the DNA double helix. Cytosine methylation is usually linked to silencing of transcription. Methylation also interacts with chromatin structure: increased CpG methylation is usually linked to heterochromatic state. (D) Changes in chromosomal structure during aging is characterized by a decrease of heterochromatic regions (symbolized by darker color) and an increase of euchromatic regions (symbolized by lighter colors).
Figure 5
Figure 5
Macroautophagy. This figure depicts macroautophagy, which is the only mechanism in cells able to remove aberrant mitochondria and large protein aggregates. (A) First, formation of a double membrane structure, the phagophore, is initiated around the target. (B) The expansion of the double membrane structure around the target will eventually form a vesicle, called autophagosome. (C) When the autophagosome fuses with a lysosome, degradation of the autophagosome’s content can take place and resulting molecular compounds can be recycled thereafter.
Figure 6
Figure 6
Signaling pathways. This figure illustrates some of the many signaling pathways that have been connected to aging. Activating interactions are shown with arrows, while inhibiting interactions are represented by bar headed lines. (A) Almost all of the age-related signaling pathways converge on the metabolic signal integrator mTORC1 complex, which includes the mTOR kinase together with RPTOR and other proteins. mTORC1 integrates stimuli to fine-tune metabolic processes, protein synthesis, cell growth, and autophagy. Downstream targets of mTORC1 include ribosomal proteins and translation initiation factors, like RPS6KB1 and EIF4EBP1, as well as ULK1, which is an activator of autophagy. As its name indicates, mTOR is the main target of rapamycin, which inhibits its function. (B) The IGF1 signaling is considered to be the main modulator that links autophagy to aging. Upregulation of this pathway leads to repression of autophagy and activation of protein synthesis by mTOR. This pathway includes many proteins, most of which have kinase activity. The PI3K enzymes transmit the signal from the IGF1 receptor by phosphorylating phosphatidylinositol molecules in the membrane, which then activate PDPK1. From here, the signal is forwarded to AKT (also known as PKB) by phosphorylation. AKT then inhibits the function of the TSC1 and TSC2 proteins, and consequently releases RHEB from inhibition. RHEB directly binds and activates the mTORC1 complex. (C) Another signaling pathway, which acts parallel to IGF1, is the TGF-β signalization. It is implicated in cellular growth control and also in tumorigenesis and inhibits autophagy. SMAD proteins transduce the TGF-β signal to downstream targets. An important target of SMAD2/4 is the FOXO gene family. (D) FOXO transcription factors have an evolutionary conserved function in aging regulation and integrate several pathways to upregulate autophagy and inhibit mTORC1. (E) Sirtuins (SIRT1/2) act contrary to the TGF-β pathway as they upregulate FOXO and thus autophagy. Resveratrol and caloric restriction exert their anti-aging effect through the activation of sirtuins. (F) The MAPK proteins were also shown to play a role in aging by regulating FOXO. They serve as important early responsive elements of different cellular stimuli and also play a role in apoptotic cell death induction in the case of UV-light damage. (G) AMPK integrates metabolite sensing information and acts contrary to the IGF1 pathway: activation of AMPK leads to down-regulation of mTOR and activation of autophagy. AMPK is the main target of metformin. mTOR, mechanistic target of rapamycin; RPTOR, regulatory associated protein of MTOR; RPS6KB1, ribosomal protein S6 kinase, 70kD, polypeptide 1; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ULK1, unc-51 like autophagy activating kinase 1; IGF1, insulin-like growth factor 1; PIK3, phosphatidylinositol-4,5-bisphosphate 3-kinase; PDPK1, 3-phosphoinositide dependent protein kinase 1; AKT, AKT serine/threonine kinase 1; TSC1, tuberous sclerosis 1; TSC2, tuberous sclerosis 2; RHEB, Ras homolog, mTORC1 binding protein b; complex 1; TGF-β, transforming growth factor β; SMAD, MAD, mothers against decapentaplegic; FOXO, forkhead box O; SIRT, sirtuin; MAPK, mitogen-activated protein kinase; AMPK, adenosine monophosphate kinase.
Figure 7
Figure 7
Mitochondria and oxidative stress. (A) Mitochondria represent the main source for reactive oxygen species (ROS) within eukaryotic cells as the oxidative respiration processes take place in the inner membrane of mitochondria, utilizing a special electron transport chain. Increased respiration rate due to metabolic changes and reduced antioxidant accessibility may also increase generation of ROS, which can damage the mitochondrial genome as well (indicated by thick arrow). (B) Accumulation of mutations in the mitochondrial genome may lead to malfunction in the electron transport chain in aberrant mitochondria that consequently produce an elevated rate of ROS. Removal of aberrant mitochondria is a key process for maintaining oxidative balance in cells.
Figure 8
Figure 8
Model organisms of aging. The figure illustrates common aging model organisms, including small animal models and large aninmal models used to study various aspetcs of aging. (AC) Yeast (Saccharomyces cerevisiae) and the invertebrates Caenorhabditis elegans and Drosophila melanogaster are ideal to experimentally study the basic, conserved mechanisms of cellular – and organismal – aging. On the other hand, they show less biological complexity than vertebrates in many aspects, and they do not naturally develop neurodegeneration. (DE) Vertebrate small animal models, like the turqoise killifish (Nothobranchius furzeri) and rodents (Mus musculus and Rattus norvegicus) are ideal to study the biological mechanisms that may be absent in invertebrates, and they can still be rather easily used in experimental studies, including genetic manipulations. However, they typically do not develop age-related neurodegeneration, and may lack many aspects of the complex social and environmental influencers of human aging. (FG) Dogs show similarities to humans in their physiology and they tend to naturally develop age-related cognitive decline. Laboratory dogs (F) are traditional large animal models in pharmacology reserach. However, the same way as other laboratory models, they do not represent the natural genetic and environmental variability typical for human populations. Family dogs, (G) on the other hand, live in the same environment as humans do, and show a special population genetic stratification, with the presence of genetically isolated, diverse populations (breeds). (H) Primates are the closest related to humans, thus they may seem to be the most appropriate animals to study human aging. However, primates are not suited for large-scale sudies for many reasons, including ethical and financial ones. Although they tend to develop human-like age-related neurodegeneration, they still lack the genetic and environmental complexity (both in the laboratory and in their natural habitats), which may influence human aging phenotypes in human populations. (I) Human aging shows many unique attributes, including a high prevalence of neurodegeneration. Age-related neurodegeneration is hard to study in most animals, and translational experiments have had many limitations so far. Brain aging may be fundamentally affected by non-genetic factors, including diet, exercise and social environment, which seem challenging to be modelled under laboratory conditions to reflect the natural circumstances of human populations.

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