Longevity Of Animals Research Articles

Classification of amyloidosis and protein misfolding disorders in animals 2024: A review on pathology and diagnosis.

Amyloidosis is a group of diseases in which proteins become amyloid, an insoluble fibrillar aggregate, resulting in organ dysfunction. Amyloid deposition has been reported in various animal species. To diagnose and understand the pathogenesis of amyloidosis, it is important to identify the amyloid precursor protein involved in each disease. Although 42 amyloid precursor proteins have been reported in humans, little is known about amyloidosis in animals, except for a few well-described amyloid proteins, including amyloid A (AA), amyloid light chain (AL), amyloid β (Aβ), and islet amyloid polypeptide-derived amyloid. Recently, several types of novel amyloidosis have been identified in animals using immunohistochemistry and mass spectrometry-based proteomic analysis. Certain species are predisposed to specific types of amyloidosis, suggesting a genetic background for its pathogenesis. Age-related amyloidosis has also emerged due to the increased longevity of captive animals. In addition, experimental studies have shown that some amyloids may be transmissible. Accurate diagnosis and understanding of animal amyloidosis are necessary for appropriate therapeutic intervention and comparative pathological studies. This review provides an updated classification of animal amyloidosis, including associated protein misfolding disorders of the central nervous system, and the current understanding of their pathogenesis. Pathologic features are presented together with state-of-the-art diagnostic methods that can be applied for routine diagnosis and identification of novel amyloid proteins in animals.

Identification of DNA methylation markers for age and Bovine Respiratory Disease in dairy cattle: A pilot study based on Reduced Representation Bisulfite Sequencing

Methylation profiles of animals are known to differ by age and disease status. Bovine respiratory disease (BRD), a complex infectious disease, primarily affects calves and has significant impact on animal welfare and the cattle industry, due to production losses, increased veterinary costs as well as animal losses. BRD susceptibility is multifactorial, influenced by both environmental and genetic factors. We have performed a pilot study to investigate the epigenetic profile of BRD susceptibility in six calves (three healthy versus three diagnosed with BRD) and age-related methylation differences between healthy calves and adult dairy cows (three calves versus four adult cows) using Reduced Representation Bisulfite Sequencing (RRBS). We identified 2537 genes within differentially methylated regions between calves and adults. Functional analysis revealed enrichment of developmental pathways including cell fate commitment and tissue morphogenesis. Between healthy and BRD affected calves, 964 genes were identified within differentially methylated regions. Immune and vasculature regulatory pathways were enriched and key candidates in BRD susceptibility involved in complement cascade regulation, vasoconstriction and respiratory cilia structure and function were identified. Further studies with a greater sample size are needed to validate these findings and formulate integration into breeding programmes aiming to increase animal longevity and disease resistance.

Therapeutic approaches targeting aging and cellular senescence in Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were "AGING," "HUNTINGTON'S DISEASE," "MUTANT HUNTINGTIN," and "CELLULAR SENESCENCE." Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as "DNA DAMAGE," "OXIDATIVE STRESS," and "AUTOPHAGY." According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro-inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients' quality of life.

Increased Reaction Vessel Surface Area Decreases the Overall Mortality Rate of Rana catesbeiana Larvae during Chemically Induced Metamorphosis

Stimulating precocious metamorphosis in anuran larvae is an important pedagogical tool for understanding vertebrate development. However, historically, artificially provoking metamorphosis by immersing tadpoles in exogenous inducing agents (e.g., thyroxine, and iodine) compromises the longevity of the experimental animals, resulting in up to 100% mortality within a week. In our undergraduate teaching lab, we house our experimental tadpoles in circular glass dishes having a surface area of 182 cm2. Over the past four academic years this lab was performed, we observed 100% mortality of experimental animals within 10, 12, or 15 days when treated with 10-5 M, 10-6 M, or 10-7 M thyroxine, respectively. Here, we investigated whether increasing the surface area to 413 cm2 using square glass dishes would reduce the mortality of the treated animals. Omnibus Kaplan-Meier survival analysis demonstrates a statistically significant decrease in mortality in tadpoles reared in the larger square dishes compared to those housed in the smaller round dishes (P < 0.05). However, increasing the surface area of our reaction vessels could not rescue survivability of those tadpoles immersed in thyroxine, but did increase survivability of control tadpoles maintained in pond water (P < 0.01), tadpoles subjected to iodine (P < 0.05) or treated with actinomycin D (P < 0.05). These data demonstrate that increasing available reaction vessel surface area reduces overall tadpole mortality during chemically modified metamorphosis in an undergraduate teaching lab setting.

Management lessons from a long‐term captive‐breeding program for a critically endangered species, Leadbeater's possum, Gymnobelideus leadbeateri

AbstractLeadbeater's possums (Gymnobelideus leadbeateri) are a critically endangered marsupial found in a restricted area of cold, wet forest in South‐Eastern Australia. The majority of Leadbeater's possums inhabit highland forest, with one outlying lowland population. In 2012, a breeding program was established for the lowland Leadbeater's possums when this genetically distinct population faced imminent extinction. Successful reproduction by highland Leadbeater's possums in the international zoo‐based population between 1970 and 2010 led to the widespread belief that the species bred readily in captivity. Lowland possums have not bred in the 2012–2021 contemporary captive conservation breeding program. This study reviewed the historic captive‐breeding data and found that of the 84% (162/194) that reached reproductive maturity; 37% of males (n = 30) and 39.5% of females (n = 32) bred, and this success was highly skewed towards a subset of highly fecund individuals (14% of females and 15% of males produced 75% and 80% of all offspring). Although lack of reproductive output in the captive lowland animals could be explained if age at mortality was lower than that of highlands possums, comparison of the longevity of highland and lowland animals had no significant difference. Conservation objectives that specify how captive breeding may support in situ recovery of wild populations are integral to the success of captive programs. A lack of reflective analysis of past husbandry records allowed misconceptions of success and approaches implemented in the management of the breeding program, reducing the benefits for the conservation of this high profile threatened species. This case study provides a lesson for the management of conservation breeding programs and illustrates the importance of well‐defined conservation objectives, integration of in situ and ex situ strategies, and the importance of objective, systematic and timely analysis of available evidence to inform management objectives and improve conservation outcomes in real time.

The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop

Animal longevity is a function of global vital organ functionality and, consequently, a complex polygenic trait. Yet, monogenic regulators controlling overall or organ-specific ageing exist, owing their conservation to their function in growth and development. Here, by using pathway analysis combined with wet-biology methods on several dynamic timelines, we identified Hnf1a as a novel master regulator of the maturation and ageing in the adult pancreatic islet during the first year of life. Conditional transgenic mice bearing suboptimal levels of this transcription factor in the pancreatic islets displayed age-dependent changes, with a profile echoing precocious maturation. Additionally, the comparative pathway analysis revealed a link between Hnf1a age-dependent regulation and immune signaling, which was confirmed in the ageing timeline of an overly immunodeficient mouse model. Last, the global proteome analysis of human islets spanning three decades of life largely backed the age-specific regulation observed in mice. Collectively, our results suggest a novel role of Hnf1a as a monogenic regulator of the maturation and ageing process in the pancreatic islet via a direct or indirect regulatory loop with immune signaling.

Продуктивность и биохимический профиль крови первотелок при повышении уровня кормления

High productivity and longevity of animals are the key challenges in modern dairy farming. In addition to high milk yields, first-calf heifers also have to increase their body weight. Due to their physiological characteristics, they are unable to consume large amounts of bulky forage to provide energy and nutrients for potential productivity. One of the ways to solve this problem is to increase the feeding level of first-calf heifers at the expense of concentrates. The assessment of the relationship between the level of feeding and the level of productivity and health of the animal was carried out by studying metabolic processes using biochemical markers of blood serum. The studies were carried out in the Moscow region for 150 days on 36 first-calf heifers, which were divided into three groups of 12 cows each according to the group-analogue principle. The control group received a ration balanced according to detailed norms for annual productivity of 8 to 9 thousand kilograms of milk per lactation. The second experimental group received a ration with increased content of metabolizable energy by 7.8% and crude protein by 8.2% of the requirement, the third group – by 15.1% and 16.4%, respectively, due to additional feeding of a targeted protein- vitamin-mineral concentrate. The researchers found that increasing the feeding level allowed to increase the live weight of first-calf heifers by 5.6% and 6.8% and the average daily milk yield by 6.4% and 9.6% in comparison with the control, and did not have a negative effect on the character of metabolism. All indicators of protein, lipid, carbohydrate and mineral metabolism were within reference values. The content of the albumin fraction in the blood serum of cows in the experimental groups was 39.7% and 39.5% of the content of total protein, while in the control group it was 36%. A significant increase in the content of the albumin fraction, by 5.12% (p=0.04) in the 2nd experimental group and by 7.24% (p=0.01) in the 3rd experimental group, with a simultaneous decrease in the content of total protein, characterizes a higher intensity of biosynthetic processes in the body associated with increased milk formation. Indicators of mineral metabolism were also within the physiological norm. The increase in magnesium content in cows of the 3rd experimental group is associated with an increase in its level in the diet of first-calf heifers. The increase in alkaline phosphatase activity indicates an increase in the functional activity of the liver, which is also associated with milk formation.

Ovarian tissue autotransplantation improves longevity in mice.

In this study, we show the improvement in life longevity in an experimental mouse model after step-by-step autologous ovarian transplantation and compare its effects with exogenic transdermal estradiol usage. This has proven to be more efficient than "traditional" hormonal replacement therapy. Despite the high speed and effectiveness of estradiol replacement deficiency in blood by its oral or transdermal use, no significant increase in the life longevity of animals and possibly in women was noted. The function of the transplanted fragment is usually limited to 6-12months. This is enough for oncofertility purposes, sometimes, but not for longevity improvement. We performed periodical tissue return (autologous transplantation), containing both the cortex and medulla in the experimental mouse model, which resulted in a statistically reliable improvement in longevity. Our experience indicates the important role of medullary ovarian factors in slowing the aging process in the body and increasing the life expectancy in the experiment. As shown, the transdermal estrogen supportive therapy for ovarian deficiency improves estrogen levels but causes much slower decreases in the follicle stimulating hormone (FSH) and luteinizing hormone (LH). Moreover, we attained the best longevity with step-by-step periodic ovarian autotransplantation, thus making "prosthetics" of ovarian function longer than it is preplanned physiologically [direct correlation between the levels of FSH and lifespan (r = 0.98)]. The experimental model we suggested could be projected to other mammals or humans as cortical transplantation provides the same results for reproduction restoration in mice and humans and even for hormone level normalization, but there is still a lack of information about anti-aging factors in the ovarian medulla and cortex. Hence, we consider that the most important factor for the anti-aging ovarian transplantation technology is to preserve and transfer both the medulla and cortex as parts of the whole ovary.

Glia-specific expression of neuropeptide receptor Lgr4 regulates development and adult physiology in Drosophila.

Similar to the human brain, Drosophila glia may well be divided into several subtypes that each carries out specific functions. Glial GPCRs play key roles in crosstalk between neurons and glia. Drosophila Lgr4 (dLgr4) is a human relaxin receptor homolog involved in angiogenesis, cardiovascular regulation, collagen remodeling, and wound healing. A recent study suggests that ilp7 might be the ligand for Lgr4 and regulates escape behavior of Drosophila larvae. Here we demonstrate that Drosophila Lgr4 expression in glial cells, not neurons, is necessary for early development, adult behavior, and lifespan. Reducing the Lgr4 level in glial cells disrupts Drosophila development, while knocking down other LGR family members in glia has no impact. Adult-specific knockdown of Lgr4 in glia but not neurons reduce locomotion, male reproductive success, and animal longevity. The investigation of how glial expression of Lgr4 contributes to this behavioral alteration will increase our understanding of how insulin signaling via glia selectively modulates neuronal activity and behavior.

Expression, not sequence, distinguishes miR-238 from its miR-239ab sister miRNAs in promoting longevity in Caenorhabditis elegans.

MicroRNAs (miRNAs) regulate gene expression by base-pairing to target sequences in messenger RNAs (mRNAs) and recruiting factors that induce translational repression and mRNA decay. In animals, nucleotides 2-8 at the 5' end of the miRNA, called the seed region, are often necessary and sometimes sufficient for functional target interactions. MiRNAs that contain identical seed sequences are grouped into families where individual members have the potential to share targets and act redundantly. A rare exception seemed to be the miR-238/239ab family in Caenorhabditis elegans, as previous work indicated that loss of miR-238 reduced lifespan while deletion of the miR-239ab locus resulted in enhanced longevity and thermal stress resistance. Here, we re-examined these potentially opposing roles using new strains that individually disrupt each miRNA sister. We confirmed that loss of miR-238 is associated with a shortened lifespan but could detect no longevity or stress phenotypes in animals lacking miR-239a or miR-239b, individually or in combination. Additionally, dozens of genes were mis-regulated in miR-238 mutants but almost no gene expression changes were detected in either miR-239a or miR-239b mutants compared to wild type animals. We present evidence that the lack of redundancy between miR-238 and miR-239ab is independent of their sequence differences; miR-239a or miR-239b could substitute for the longevity role of miR-238 when expressed from the miR-238 locus. Altogether, these studies disqualify miR-239ab as negative regulators of aging and demonstrate that expression, not sequence, dictates the specific role of miR-238 in promoting longevity.

Origin and distribution pattern of pelvic limb nerves of a Bengal tiger (Panthera tigris tigris).

The Bengal tiger (Panthera tigris tigris) is a species belonging to the Felidae family. In Argentina, tigers are currently only found in captivity. The longevity of individual animals in human-controlled environments depends on proper management and practices that prioritize animal welfare. Regular veterinary care is essential to maintain optimal health conditions. Professionals must have a comprehensive understanding of the anatomy and physiology of tigers to effectively perform medical procedures and administer treatments. The study described in the text focuses on the trajectory and distribution of nerves in the pelvic limb of a Bengal tiger specimen, providing detailed dissection findings. The results revealed that the lumbosacral plexus is formed from the ventral rami of the LIV, LV, LVI, LVII, SI, SII and SIII nerves. Among the observations to highlight is the great development of the nerves N. cutaneus femoris lateralis and N. cutaneus femoris caudalis some differences were observed in the distribution of the N. femoralis and N. obturatorius; the N. ischiadicus, together with its division into the fibularis communis and tibialis nerves, showed the same configuration observed in other cats. Finally, it was observed that the nerves N. gluteus cranialis and N. gluteus caudalis also originated from the truncus lumbosacralis. The similarities and differences with studies carried out on other cats are relevant and provide anatomical data for medical procedures in the Bengal tiger.

Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell nonautonomous autophagic and peroxidase activity

Accumulating evidence has demonstrated the presence of intertissue-communication regulating systemic aging, but the underlying molecular network has not been fully explored. We and others previously showed that two basic helix-loop-helix transcription factors, MML-1 and HLH-30, are required for lifespan extension in several longevity paradigms, including germlineless Caenorhabditis elegans. However, it is unknown what tissues these factors target to promote longevity. Here, using tissue-specific knockdown experiments, we found that MML-1 and its heterodimer partners MXL-2 and HLH-30 act primarily in neurons to extend longevity in germlineless animals. Interestingly, however, the downstream cascades of MML-1 in neurons were distinct from those of HLH-30. Neuronal RNA interference (RNAi)-based transcriptome analysis revealed that the glutamate transporter GLT-5 is a downstream target of MML-1 but not HLH-30. Furthermore, the MML-1-GTL-5 axis in neurons is critical to prevent an age-dependent collapse of proteostasis and increased oxidative stress through autophagy and peroxidase MLT-7, respectively, in long-lived animals. Collectively, our study revealed that systemic aging is regulated by a molecular network involving neuronal MML-1 function in both neural and peripheral tissues.

100 years flashback

100 years flashback

Genotoxicity Signatures near Brine Outflows from Desalination Plants in the Levant

(1) Background: Desalination is a developing industry that keeps expanding, nowadays counting >15,000 infrastructures worldwide. A byproduct of the desalination process is concentrated brine, further containing operational chemicals, including antiscalants and coagulants. Yet, the potential genotoxic impacts of the inclusive brine are inadequately studied. (2) Methods: In vitro and in vivo assays were used to test the impacts of a representative antiscalant and a coagulant. The model cnidarian Nematostella vectensis was employed to assess the impacts of the tested pollutants on animal longevity. Additionally, the genotoxicity of seawater sampled near four desalination plants was tested using the comet assay. (3) Results: In vitro analyses of the antiscalant and coagulant revealed neither genotoxic nor cytotoxic effects at environmentally relevant concentrations, but they were destructive to whole organisms (N. vectensis) at various developmental stages. Part of the seawater samples from sites near desalination plants were genotoxic, revealing ephemeral and mosaic genotoxicity. Since desalination plants are situated in highly anthropogenic-impacted areas, it is impossible at this stage to evaluate the possible contribution of the brine to overall marine genotoxicity. (4) Conclusions: Exact desalination-associated chemicals and the brine itself should be evaluated directly for potential genotoxicity.

Ensheathing glia promote increased lifespan and healthy brain aging.

Glia have an emergent role in brain aging and disease. In the Drosophila melanogaster brain, ensheathing glia function as phagocytic cells and respond to acute neuronal damage, analogous to mammalian microglia. We previously reported changes in glia composition over the life of ants and fruit flies, including a decline in the relative proportion of ensheathing glia with time. How these changes influence brain health and life expectancy is unknown. Here, we show that ensheathing glia but not astrocytes decrease in number during Drosophila melanogaster brain aging. The remaining ensheathing glia display dysregulated expression of genes involved in lipid metabolism and apoptosis, which may lead to lipid droplet accumulation, cellular dysfunction, and death. Inhibition of apoptosis rescued the decline of ensheathing glia with age, improved the neuromotor performance of aged flies, and extended lifespan. Furthermore, an expanded ensheathing glia population prevented amyloid-beta accumulation in a fly model of Alzheimer's disease and delayed the premature death of the diseased animals. These findings suggest that ensheathing glia play a vital role in regulating brain health and animal longevity.

Reproductive traits of cows of Holstein breed and dynamics of their changes during productive life

In order to obtain maximum milk productivity of cows, it is necessary to constantly maintain a high level of reproduction traits of cows in the herd to ensure timely eff ective insemination of them for the annual production of calves. The economy of dairy farming, the level of breeding work, the longevity of animals depends on the state of reproduction of the herd. The purpose of the research was to study the reproductive traits of cows of Holstein breed and the dynamics of their changes during productive life. The research was carried out on the basis of the Agricultural Production Cooperative “Plamya”, a milk production enterprise where Holstein cattle are bred. In order to conduct the study, the indicators of the reproductive traits of cows of the entire productive herd were evaluated in dynamics over 5 years of production use. The material for the analysis of the dynamics of change was taken from the database of the information and analytical system “SELEX-Dairy cattle”. Thus, it was found that during the study period the annual calf crop increased by 102,4 % or by 2 calves. The average number of inseminations per effective one was 2,1 doses over the period. In the period from 2017 to 2021, in the herd the duration of the open days period ranged from 128 to 140 days. The best indicator was noted in 2019. On average, for the herd over a fi ve-year period, there was an increase in the duration of the open days period by 12 days compared to 2017 data. As a result of a comprehensive analysis of the state of reproduction traits of cows in the herd, it was found that the indicators of reproductive trais of cows had a slight deviation from the threshold (normative) values, which indicates a fairly high level of breeding work carried out by specialists of the farm.

Ovarian papillary carcinoma in a Mongolian gerbil (Meriones unguiculatus)

Neoplasms are among the most impacting disease diagnoses in veterinary medicine and have become increasingly common due to the greater longevity of animals as living conditions improved. The Mongolian gerbil is a small rodent species that has become popular recently. In these animals, the occurrence of neoplastic processes is relatively common, mainly tumors of the ventral gland in males and ovarian tumors in females. This work aims to report an ovarian tumor in a Mongolian gerbil Meriones unguiculatus Milne-Edwards 1867 (Rodentia, Muridae). At the initial presentation, the animal had dyspnea, prostration, and increased abdominal volume in the topography of the right ovary of approximately 2 cm. The animal was submitted to exploratory laparotomy because of the emergency nature of the case and the owners’ refusal of additional exams due to financial restrictions. Thus, an ovariohysterectomy was performed, followed by a histopathological examination. The histopathology revealed an ovarian papillary carcinoma affecting both ovaries and cystic endometrial hyperplasia. With surgical removal and drainage of the thoracic fluid, the animal showed good recovery, with general improvement and return to regular activity, with a life expectancy of two years. Currently, the demand for specialized veterinarians for unconventional pets is increasing. This condition allows owners to raise their animals more properly, favoring greater longevity. Knowledge about the prevalence and incidence of diseases in different species is of enormous relevance in establishing the appropriate therapy, improving life quality, and increasing life expectancy in animals’ lives.

Reproductive capacity and milk production of cows depending on their physio-logical status during lactation

Due to violation of husbandry, feeding, milking, non-observance of sanitary requirements, especially in postpartum period, cases of endometritis, mastitis and limb diseases in cows increase in conditions of intensive cattle breeding. These diseases adversely affect reproductive and productive qualities of animals, thus causing great financial losses to agribusiness. Therefore, increasing longevity of animals, reducing percentage of their elimination due to various diseases, reducing risk of economically significant diseases in dairy herds by selecting highly productive animals with high resistance to common diseases are relevant. The aim of the research was to study phenotypic relationship between fertility level and milk production of black-motley Holsteinized cows with different diseases at the farm in Moscow region. The research materials were 1234 records of diseases - endometritis, mastitis and limb diseases - obtained from veterinary outpatient logs (2015-2021) of the breeding organization. Information about 5 signs of milk productivity and 3 signs of fertility of the studied population of black-motley Holsteinized dairy cattle was taken from Seleks database. According to the results, significant (p 0.01) increase was observed in sick animals in comparison with healthy ones: number of inseminations per lactation - b y 33.5 %, open days - b y 7.3 %, milk days - b y 4.35 %. Milk yield was higher by 19.4 % (p 0.01), fat and protein mass fraction - by 0.32 and 0.33 % (p 0.01), respectively, fat and protein yield - b y 82 and 69 kg (p 0.01), respectively, compared to healthy animals. When comparing the indices in animals with one, two and three diseases, significant differences were obtained both between the groups with single diseases and complexes. For fertility traits, the indices increased significantly with the number of diseases from 4 to 20 % for individual traits. For milk production traits, there was a tendency for indices to decrease with increasing number of diseases.

Sirtuins are Not Conserved Longevity Genes.

It is central to biology that sequence conservation suggests functional conservation. Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions after reproductive maturity. Though the yeast SIR2 gene was nominated as a longevity gene based on extended replicative longevity of old mother cells, this is not a selected trait: SIR2 is selected against in chronological aging and the direct targets of SIR2 in replicative lifespan are not conserved. Though it would be difficult to imagine how a gene that advantages 1 in 5 million yeast cells could have anticipated causes of aging in animals, overexpression of SIR2 homologs was tested in invertebrates for longevity. Because artifactual positive results were reported years before they were sorted out and because it was not known that SIR2 functions as a pro-aging gene in yeast chronological aging and in flies subject to amino acid deprivation, a global pursuit of longevity phenotypes was driven by a mixture of framing bias, confirmation bias and hype. Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes. Acknowledging that a few positive associations between sirtuins and longevity have been identified after thousands of person-years and billions of dollars of effort, we review the data and suggest rejection of the notions that sirtuins 1) have any specific connection to lifespan in animals and 2) are primary mediators of the beneficial effects of NAD repletion.

Sirtuin Evolution at the Dawn of Animal Life.

Sirtuins are a family of proteins that protect against cellular injury and aging; understanding their evolution should reveal fundamental mechanisms governing longevity. “Early-branching” animals such as sea sponges and jellyfish have been understudied in previous analyses of sirtuin diversity. These organisms not only hold important positions at the base of the evolutionary tree, but also have unique aging dynamics that defy convention, such as quasi-immortality and high regenerative capacity. In this study, we survey the evolution of sirtuin proteins in animals, with a focus on the oldest living lineages. We describe previously unrecognized expansions of “Class IV” and “Class I” sirtuins around the origin of animals, raising the number of sirtuin families in the last common ancestor to at least nine. Most of these undescribed sirtuins have been lost in vertebrates and other bilaterian animals. Our work also clarifies the evolution of PNC1 and NAMPT enzymes that carry out the rate-limiting step in sirtuin-related NAD+ biosynthesis. The genes for PNC1 and NAMPT enzymes were both present in the first animals, with the genes being lost a minimum of 11 and 13 times, respectively, over the course of animal evolution. We propose that species with these ancestral gene repertoires are ideal model organisms for studying the genetic regulation of animal longevity and will provide clues to increasing longevity in humans.