Lifespan Regulation Research Articles

Anti-aging effect of glycerophosphocholine in Steinernema kraussei 0657L

Glycerophosphocholine (GPC) is a water-soluble small molecule found naturally in humans and foods such as milk and soybeans. It can activate the IIS pathway by regulating the expression of daf-2, ins-18 and daf-16 genes, sek-1 and skn-1 genes of MAPK pathway, sod-3, ctl-1, gst-4 and other antioxidant genes. GPC can relieve symptoms related to aging in organisms. The aim of this study was to probe the effects of GPC on the longevity and stress resistance of the entomopathogenic nematode (EPN) Steinernema kraussei 0657L strain. The results showed that the lifespan of S. kraussei 0657L was significantly prolonged by 50 mM GPC treatment, which was 54.55% longer than that of the control (0 mM GPC). GPC significantly inhibited reactive oxygen species (ROS) and lipofuscin accumulation, but the body size and fecundity of S. kraussei 0657L had little changed. At the same time, the longevity of S. kraussei 0657L exposed to heat shock and UV-B radiation was significantly prolonged than that with no external stress. GPC supplementation increased the activity of antioxidant enzymes and corresponding gene expression. Under treatment with 50 mM GPC, the activities of superoxide dismutase and catalase were increased by 1.90- and 4.13-fold, respectively, the expression of the sod-3 and ctl-1 genes was increased by 3.60- and 0.60-fold, respectively, and harmful reactive oxygen species were removed. In addition, the expression levels of the ins-18, skn-1, sek-1 and gst-4 genes related to the insulin/IGF-1 signaling pathway were upregulated 1.04-, 1.84-, 2.21- and 1.24-fold, respectively. These results indicate that GPC is mainly involved in the lifespan regulation of S. kraussei 0657L and plays an important role in resistance to external stress by activating the insulin/IGF-1 signaling pathway and downstream PI3K/MAPK kinase, creating a new idea for improving the commercial efficacy of S. kraussei. It also laid a theoretical foundation for its further efficient development and utilization in the field of biological control.

Glucosylglycerol and proline reverse the effects of glucose on Rhodosporidium toruloides lifespan.

Rhodosporidium toruloides is a novel cell factory used to synthesis carotenoids, biosurfactants, and biofuel feedstocks. However, research on R. toruloides has generally centred on the manufacture of biochemicals, while analyses of its longevity have received scant attention. Understanding of R. toruloides longevity under different nutrient conditions could help to improve its biotechnological significance and metabolite production. Glucosylglycerol (GG) and proline are osmoprotectants that could revert the harmful effects of environmental stress. This study examined how GG and proline affect R. toruloides strain longevity under glucose nutrimental stress. Herein, we provide evidence that GG and proline enhance cell performance and viability. These compatible solutes neutralises the pro-ageing effects of high glucose (10% glucose) on the yeast cell and reverse its cellular stress. GG exhibits the greatest impact on lifespan extension at 100mM, whereas proline exerts effect at 2mM. Our data reveal that these compounds significantly affect the culture medium osmolarity. Moreso, GG and proline decreased ROS production and mitohormetic lifespan regulation, respectively. The data indicates that these solutes (proline and GG) support the longevity of R. toruloides at a pro-ageing high glucose culture condition.

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging.

The gonad has become a central organ for understanding aging in C. elegans, as removing the proliferating stem cells in the germline results in significant lifespan extension. Similarly, when starvation in late larval stages leads to the quiescence of germline stem cells the adult nematode enters reproductive diapause, associated with an extended lifespan. This review summarizes recent advancements in identifying the mechanisms behind gonad-mediated lifespan extension, including comparisons with other nematodes and the role of lipid signaling and transcriptional changes. Given that the gonad also mediates lifespan regulation in other invertebrates and vertebrates, elucidating the underlying mechanisms may help to gain new insights into the mechanisms and evolution of aging.

CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan.

CYP-14 members of the Caenorhabditis elegans (C. elegans) Cytochrome P450 (CYP) enzyme family, plays important roles in mitochondrial dysfunction, detoxification, lipid metabolism, defense and lifespan regulation. The review identifies CYP-14 members: cyp-14A1, cyp-14A2, cyp-14A3, cyp-14A4, cyp-14A5 and their homology with human CYP families. Despite limited studies on C. elegans cyp-14 members, the findings unraveled their complex crosstalk between mitochondrial stress, detoxification mechanisms, and lifespan regulation, emphasizing the complexity of these interconnected pathways as well as how their regulation depends on environmental cues changes including pH, nutrients, ROS and chemical stressors. The review underscores the translational relevance to human health, shedding light on potential human homologues and their implications in age-related, metabolic and respiratory diseases. Among other genes, cyp-14A2 and cyp-14A4 predominate the mitochondrial function, heat resistance, lipid metabolism, detoxification and lifespan pathways. In conclusion, these insights pave the way for future research, offering promising avenues for therapeutic interventions targeting CYP-14 activity to address age-related diseases and promote healthy aging.

Feeding on lactic acid bacteria isolated from food extends the lifespan of Caenorhabditis elegans.

Lactic acid bacteria (LAB) contribute to human health, and LAB functionality has been studied using Caenorhabditis elegans as an alternative host. However, many studies have focused on the efficacy of a single strain of LAB, and few reports have compared various LAB strains. In this study, we examined the effects of 15 strains of LAB isolated from vegetables, meat, and fermented foods on nematode longevity and healthy lifespan. To reduce the frequency of laborious survival observations, we performed a lifespan assay on agar plates containing 2'-deoxy-5-fluorouridine (FUdR), which inhibits egg hatching and prevents generation mixing. Four beneficial strains showed significant lifespan extension and increased spontaneous nematode mobility, regardless of treatment with or without FUdR and the frequency of survival observation. These results suggested increased longevity and an extended healthy lifespan, confirming the reliability of our method. The four strains are expected to show anti-ageing effects besides longevity and have effects on age-related degenerative diseases. Our labor-saving method can be used as an alternative to conventional methods and enable simultaneous screening of multiple strains. Future research could explore factors contributing to lifespan regulation by comparing and verifying differential strain effects on lifespan.

Sirtuins in kidney health and disease.

Sirtuins (SIRTs) are putative regulators of lifespan in model organisms. Since the initial discovery that SIRTs could promote longevity in nematodes and flies, the identification of additional properties of these proteins has led to understanding of their roles as exquisite sensors that link metabolic activity to oxidative states. SIRTs have major roles in biological processes that are important in kidney development and physiological functions, including mitochondrial metabolism, oxidative stress, autophagy, DNA repair and inflammation. Furthermore, altered SIRT activity has been implicated in the pathophysiology and progression of acute and chronic kidney diseases, including acute kidney injury, diabetic kidney disease, chronic kidney disease, polycystic kidney disease, autoimmune diseases and renal ageing. The renoprotective roles of SIRTs in these diseases make them attractive therapeutic targets. A number of SIRT-activating compounds have shown beneficial effects in kidney disease models; however, further research is needed to identify novel SIRT-targeting strategies with the potential to treat and/or prevent the progression of kidney diseases and increase the average human healthspan.

Unusual functions of insect vitellogenins: minireview.

Insect vitellogenins are an intriguing class of complex proteins. They primarily serve as a source of energy for the developing embryo in insect eggs. Vitellogenesis is a complex hormonally and neurally controlled process that command synthesis of vitellogenin molecules and ensures their transport from the female fat bodies or ovarial cells into eggs. The representatives of all insect hormones such as juvenile hormones, ecdysteroids, and neurohormones participate in vitellogenesis, but juvenile hormones (most insect species) and ecdysteroids (mostly Diptera) play the most important roles in the process. Strikingly, not only insect females, but also males have been reported to synthesize vitellogenins indicating their further utility in the insect body. Indeed, it has recently been found that vitellogenins perform a variety of biological functions in the insect body. They participate in defense reactions against entomopathogens such as nematodes, fungi, and bacteria, as well as against venoms such as the honeybee Apis mellifera venom. Interestingly, vitellogenins are also present in the venom of the honeybee itself, albeit their exact role is unknown; they most likely increase the efficacy of the venom in the victim's body. Within the bee's body vitellogenins contribute to the lifespan regulation as anti-aging factor acting under tight social interactions and hormonal control. The current minireview covers all of these functions of vitellogenins and portrays them as biologically active substances that play a variety of significant roles in both insect females and males, and not only acting as passive energy sources for developing embryo.

GENES FROM PEROXISOME AND INTEGRATED STRESS RESPONSE IN REGULATION OF HUMAN LONGEVITY

Abstract Dietary/caloric restriction shares pathways with peroxisome, a cellular organelle that regulates the synthesis and turnover of complex lipids. PEX3, a peroxisomal biogenesis factor involved in selective type of autophagy. EIF2AK4, a sensor of amino acid deprivation in the integrated stress response (ISR) involved in lifespan regulation. We hypothesize that interplay between EIF2AK4 and PEX3 is associated with human survival. We applied logistic regression model with the interaction term to the analysis of Health and Retirement Study (HRS) and UK Biobank (UKB) parents data to test whether interactions of SNPs from the EIF2AK4 and SNPs from the PEX3 are associated with the dichotomous survival trait (ST) with case group defined as: lifespan ≥ 85; and control as: 75 ≤ (lifespan or age at last follow-up) < 85. Analyses of HRS data showed that interactions between SNPs rs4924405, rs2250402, rs8031319, rs16970049, rs3816899, rs16970112, rs2412459 from the EIF2AK4 gene and SNP rs161070 from the PEX3 gene are significantly associated with ST. In the UKB data, interactions of rs161070 from the PEX3 gene and rs7176881 and rs117778159 SNPs from the EIF2AK4 gene showed nominally significant associations with ST. Analyses of linkage disequilibrium (LD) between the EIF2AK4 SNPs detected in HRS and UKB data showed that their LD are close to the highest values for SNPs with allele frequencies specific for detected variants. Our results confirm association of interplay between EIF2AK4 and PEX3 with human longevity. They also show how information from experimental studies could be transformed to the form useful for human applications.

STRATEGIES OF LIFESPAN REGULATION WITHIN AND ACROSS SPECIES

Abstract Lifespan varies within and across species, but the general principles of its control remain unclear. We conducted multi-tissue RNA-seq analyses across mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed new longevity interventions. We further developed a transcriptomic clock that quantifies progression through lifespan and reports the effects of longevity interventions. Overall, this work uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for quantifying aging and discovering longevity interventions.

A pair of RNA binding proteins inhibit ion transporter expression to maintain lifespan.

Regulation of lifespan by transcription factors has been well established. More recently, a role for RNA binding proteins (RBPs) in regulating lifespan has also emerged. In both cases, a major challenge is to determine which regulatory targets are functionally responsible for the observed lifespan phenotype. We recently identified a pair of neuronal RBPs, exc-7/ELAVL and mbl-1/Muscleblind, which in Caenorhabditis elegans display synthetic (nonadditive) lifespan defects: single mutants do not affect lifespan, but exc-7; mbl-1 double mutants have strongly reduced lifespan. Such a strong synthetic phenotype represented an opportunity to use transcriptomics to search for potential causative targets that are synthetically regulated. Focus on such genes would allow us to narrow our target search by ignoring the hundreds of genes altered only in single mutants, and provide a shortlist of synthetically regulated candidate targets that might be responsible for the double mutant phenotype. We identified a small handful of genes synthetically dysregulated in double mutants and systematically tested each candidate gene for functional contribution to the exc-7; mbl-1 lifespan phenotype. We identified 1 such gene, the ion transporter nhx-6, which is highly upregulated in double mutants. Overexpression of nhx-6 causes reduced lifespan, and deletion of nhx-6 in an exc-7; mbl-1 background partially restores both lifespan and healthspan. Together, these results reveal that a pair of RBPs mediate lifespan in part by inhibiting expression of an ion transporter, and provide a template for how synthetic phenotypes (including lifespan) can be dissected at the transcriptomic level to reveal potential causative genes.

DNA methylation extends lifespan in the bumblebee Bombus terrestris.

Epigenetic alterations are a primary hallmark of ageing. In mammals, age-related epigenetic changes alter gene expression profiles, disrupt cellular homeostasis and physiological functions and, therefore, promote ageing. It remains unclear whether ageing is also driven by epigenetic mechanisms in invertebrates. Here, we used a pharmacological hypomethylating agent (RG108) to evaluate the effects of DNA methylation (DNAme) on lifespan in an insect-the bumblebee Bombus terrestris. RG108 extended mean lifespan by 43% and induced the differential methylation of genes involved in hallmarks of ageing, including DNA damage repair and chromatin organization. Furthermore, the longevity gene sirt1 was overexpressed following the treatment. Functional experiments demonstrated that SIRT1 protein activity was positively associated with lifespan. Overall, our study indicates that epigenetic mechanisms are conserved regulators of lifespan in both vertebrates and invertebrates and provides new insights into how DNAme is involved in the ageing process in insects.

Sis2 regulates yeast replicative lifespan in a dose-dependent manner

Application of microfluidic platforms facilitated high-precision measurements of yeast replicative lifespan (RLS); however, comparative quantification of lifespan across strain libraries has been missing. Here we microfluidically measure the RLS of 307 yeast strains, each deleted for a single gene. Despite previous reports of extended lifespan in these strains, we found that 56% of them did not actually live longer than the wild-type; while the remaining 44% showed extended lifespans, the degree of extension was often different from what was previously reported. Deletion of SIS2 gene led to the largest RLS increase observed. Sis2 regulated yeast lifespan in a dose-dependent manner, implying a role for the coenzyme A biosynthesis pathway in lifespan regulation. Introduction of the human PPCDC gene in the sis2Δ background neutralized the lifespan extension. RNA-seq experiments revealed transcriptional increases in cell-cycle machinery components in sis2Δ background. High-precision lifespan measurement will be essential to elucidate the gene network governing lifespan.

Promoting longevity with less cancer: The 2022 International Conference on Aging and Cancer

AbstractAging and cancer are increasingly becoming big challenges for public health worldwide due to increased human life expectancy. Meanwhile, aging is one of the major risk factors for cancer. In December 2019, the first International Conference on Aging and Cancer was held in Haikou, Hainan province (island), China, preluding the establishment of the International Center for Aging and Cancer (ICAC) at Hainan, an institute dedicated to the research at the intersection of aging and cancer. Since then, the ICAC has hosted the annual conference each December in Hainan. The 2022 ICAC conference, with the theme of “promoting longevity with less cancer,” invited 17 internationally renowned scientists to share their new research and insights. Topics included DNA methylation in rejuvenation, development, and cellular senescence; lifespan regulation and longevity manipulation; metabolism and aging; cellular senescence and diseases; and novel therapeutics for cancer and antiaging/anticancer drug discovery. The forum highlighted the interconnectedness of aging and senescence with cancer evolution and risk. Although there is hope for preventing diseases like cancer by modulating systems that also control lifespan, attention has to be paid to the conflicting needs and competing demands in human biology.

The Saccharomyces cerevisiae acetyltransferase Gcn5 exerts antagonistic pleiotropic effects on chronological ageing.

Compared to replicative lifespan, epigenetic regulation of chronological lifespan (CLS) is less well understood in yeast. Here, by screening all the viable mutants of histone acetyltransferase (HAT) and histone deacetylase (HDAC), we demonstrate that Gcn5, functioning in the HAT module of the SAGA/SLIK complex, exhibits an epistatic relationship with the HDAC Hda1 to control the expression of starvation-induced stress response and respiratory cell growth. Surprisingly, the gcn5Δ mutants lose their colony-forming potential early in the stationary phase but display a longer maximum CLS than their WT counterparts, suggesting the contradictory roles of Gcn5 in lifespan regulation. Integrative analyses of the transcriptome, metabolome and ChIP assays reveal that Gcn5 is necessary for the activation of two regulons upon glucose starvation: the Msn2/4-/Gis1-dependent stress response and the Cat8-/Adr1-mediated metabolic reprogramming, to enable pro-longevity characteristics, including redox homeostasis, stress resistance and maximal storage of carbohydrates. The activation of Cat8-/Adr1-dependent regulon also promotes the pyruvate dehydrogenase (PDH) bypass, leading to acetyl-CoA synthesis, global and targeted H3K9 acetylation. Global H3K9 acetylation levels mediated by Gcn5 and Hda1 during the transition into stationary phase are positively correlated with senescent cell populations accumulated in the aged cell cultures. These data suggest that Gcn5 lies in the centre of a feed-forward loop between histone acetylation and starvation-induced gene expression, enabling stress resistance and homeostasis but also promoting chronological ageing concomitantly.

Autophagy impairment and lifespan reduction caused by Atg1 RNAi or Atg18 RNAi expression in adult fruit flies (Drosophila melanogaster).

Autophagy, an autophagosome and lysosome-based eukaryotic cellular degradation system, has previously been implicated in lifespan regulation in different animal models. In this report, we show that expression of the RNAi transgenes targeting the transcripts of the key autophagy genes Atg1 or Atg18 in adult fly muscle or glia does not affect the overall levels of autophagosomes in those tissues and does not change the lifespan of the tested flies but the lifespan reduction phenotype has become apparent when Atg1 RNAi or Atg18 RNAi is expressed ubiquitously in adult flies or after autophagy is eradicated through the knockdown of Atg1 or Atg18 in adult fly adipocytes. Lifespan reduction was also observed when Atg1 or Atg18 was knocked down in adult fly enteroblasts and midgut stem cells. Overexpression of wild-type Atg1 in adult fly muscle or adipocytes reduces the lifespan and causes accumulation of high levels of ubiquitinated protein aggregates in muscles. Our research data have highlighted the important functions of the key autophagy genes in adult fly adipocytes, enteroblasts, and midgut stem cells and their undetermined roles in adult fly muscle and glia for lifespan regulation.

Evolutionary analysis of the mTOR pathway provide insights into lifespan extension across mammals

BackgroundLifespan extension has independently evolved several times during mammalian evolution, leading to the emergence of a group of long-lived animals. Though mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is shown as a central regulator of lifespan and aging, the underlying influence of mTOR pathway on the evolution of lifespan in mammals is not well understood.ResultsHere, we performed evolution analyses of 72 genes involved in the mTOR network across 48 mammals to explore the underlying mechanism of lifespan extension. We identified a total of 20 genes with significant evolution signals unique to long-lived species, including 12 positively selected genes, four convergent evolution genes, and five longevity associated genes whose evolution rate related to the maximum lifespan (MLS). Of these genes, four positively selected genes, two convergent evolution genes and one longevity-associated gene were involved in the autophagy response and aging-related diseases, while eight genes were known as cancer genes, indicating the long-lived species might have evolved effective regulation mechanisms of autophagy and cancer to extend lifespan.ConclusionOur study revealed genes with significant evolutionary signals unique to long-lived species, which provided new insight into the lifespan extension of mammals and might bring new strategies to extend human lifespan.

Compartment-driven imprinting of intestinal CD4 T cells in inflammatory bowel disease and homeostasis.

The mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T-cell populations. Human CD4 T-cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remain incompletely understood. We performed flow cytometry, bulk, and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8αα, regulatory T cells (Tregs), CD69- and CD69high Trm T cells) in controls and Crohn's disease (CD) patients (paired non-inflamed and inflamed). Inflammation results in alterations of the CD4 T-cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T-cell activation, increased IFNγ responses, and an effector Treg profile. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. In summary, inflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T-cell imprinting, driven by shared regulators, between the lamina propria and the epithelium. The main consequence of intraepithelial adaptation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium.

Abstract P1172: Shear-mediated Remodeling Of Platelet Surface Glycosylation: How Can Platelets Trim Their Sugar Coats?

Mechanical circulatory support (MCS) is associated with bleeding complications often requiring multiple transfusions or reoperation. Hypershear stress within device-supported circulation promotes platelet dysfunction associated with pro-apoptosis, impaired aggregation, and microvesiculation - all contributors to bleeding. Recent studies showed that glycosylation of surface receptors, i.e. “ sugar coat ,” plays a major role in the regulation of platelet function and lifespan. We tested the hypothesis that shear stress promotes platelet surface deglycosylation by increasing platelet glycosidase activity. Methods: Human platelets were obtained from ACD-anticoagulated blood via gel filtration on Sepharose 2B. Platelets were exposed to neuraminidase and continuous shear stress in a hemodynamic shearing device. Platelets were stained with fluorophore-conjugated lectins binding terminal sialic acids (SNA I, MAL II) and galactose (ECA), anti-CD41 and anti-CD42a a/b. Multi-colored flow cytometry was used to quantify platelet surface glycosylation. Neuraminidase and galactosidase activities of intact and lysed platelets were measured using enzyme-specific fluorogenic substrates. Results: Exposure to shear stress and neuraminidase induced a significant decrease in platelet 2,6-sialylation and galactosylation, while 2,3-sialylation remained unaltered. Neuraminidase reinforced shear-mediated platelet desialylation, causing a prominent decrease in SNA binding even at low shear, and increased platelet galactose levels by unmasking the galactose residues capped by sialic acids. Shear stress resulted in a 9.5-fold increase in platelet neuraminidase and a 1.4-fold increase in galactosidase activities vs their basal levels. Neutral neuraminidase and galactosidase were upregulated by shear, while acidic isoforms did not increase, suggesting that other than lysosomal glycosidase pools are involved. Shear stress promotes platelet deglycosylation via upregulation of platelet neuraminidase and galactosidase activities. Developing therapeutic strategies for the preservation of platelet glycosylation offers significant translational potential for the pharmacologic management of MCS platelet dysfunction and bleeding.

Comparisons of lifespan and stress resistance between sexes in Drosophila melanogaster

Animals exhibit different extents of sexual dimorphism in a variety of phenotypes. Sex differences in longevity, one of the most complex life history traits, have also been reported. Although lifespan regulation has been studied extensively in the fruit fly, Drosophila melanogaster, the sex differences in lifespan have not been consistent in previous studies. To explore this issue, we revisited this question by examining the lifespan and stress resistance of both sexes among 15 inbred strains. We first found positive correlations between males and females from the same strain in terms of lifespan and resistance to starvation and desiccation stress. Although the lifespan difference between male and female flies varied greatly depending on the strain, males across all strains collectively had a longer lifespan. In contrast, females showed better resistance to starvation and desiccation stress. We also observed greater variation in lifespan and resistance to starvation and desiccation stress in females. Unexpectedly, there was no notable correlation observed between lifespan and the three types of stress resistance in either males or females. Overall, our study provides new data regarding sexual dimorphism in fly lifespan and stress resistance; this information may promote the investigation of mechanisms underlying longevity in future research.

Large-scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals.

Lifespan varies significantly among mammals, with more than 100-fold difference between the shortest and longest living species. This natural difference may uncover the evolutionary forces and molecular features that define longevity. To understand the relationship between gene expression variation and longevity, we conducted a comparative transcriptomics analysis of liver, kidney, and brain tissues of 103 mammalian species. We found that few genes exhibit common expression patterns with longevity in the three organs analyzed. However, pathways related to translation fidelity, such as nonsense-mediated decay and eukaryotic translation elongation, correlated with longevity across mammals. Analyses of selection pressure found that selection intensity related to the direction of longevity-correlated genes is inconsistent across organs. Furthermore, expression of methionine restriction-related genes correlated with longevity and was under strong selection in long-lived mammals, suggesting that a common strategy is utilized by natural selection and artificial intervention to control lifespan. Our results indicate that lifespan regulation via gene expression is driven through polygenic and indirect natural selection.