Levels of palmitic acid ester of hydroxystearic acid (PAHSA) are reduced in the breast milk of obese mothers

To achieve optimal development of a newborn, breastfeeding is extensively recommended, but little is known about the role of non-nutritive bioactive milk components. We aimed to characterize the fatty acid esters of hydroxy fatty acids (FAHFAs), namely palmitic acid hydroxystearic acids (PAHSAs)—endogenous lipids with anti-inflammatory and anti-diabetic properties, in human breast milk.Breast milk samples from 30 lean (BMI = 19–23) and 23 obese (BMI > 30) women were collected 72 h postpartum. Adipose tissue and milk samples were harvested from C57BL/6J mice. FAHFA lipid profiles were measured using reverse phase and chiral liquid chromatography-mass spectrometry method.PAHSA regioisomers as well as other FAHFAs were present in both human and murine milk. Unexpectedly, the levels of 5-PAHSA were higher relative to other regioisomers. The separation of both regioisomers and enantiomers of PAHSAs revealed that both R- and S-enantiomers were present in the biological samples, and that the majority of the 5-PAHSA signal is of R configuration. Total PAHSA levels were positively associated with weight gain during pregnancy, and 5-PAHSA as well as total PAHSA levels were significantly lower in the milk of the obese compared to the lean mothers.Our results document for the first time the presence of lipid mediators from the FAHFA family in breast milk, while giving an insight into the stereochemistry of PAHSAs. They also indicate the negative effect of obesity on 5-PAHSA levels. Future studies will be needed to explore the role and mechanism of action of FAHFAs in breast milk.     

Artifactual FA dimers mimic FAHFA signals in untargeted metabolomics pipelines

FA esters of hydroxy FAs (FAHFAs) are lipokines with extensive structural and regional isomeric diversity that impact multiple physiological functions, including insulin sensitivity and glucose homeostasis. Because of their low molar abundance, FAHFAs are typically quantified using highly sensitive LC-MS/MS methods. Numerous relevant MS databases house in silico-spectra that allow identification and speciation of FAHFAs. These provisional chemical feature assignments provide a useful starting point but could lead to misidentification. To address this possibility, we analyzed human serum with a commonly applied high-resolution LC-MS untargeted metabolomics platform. We found that many chemical features are putatively assigned to the FAHFA lipid class based on exact mass and fragmentation patterns matching spectral databases. Careful validation using authentic standards revealed that many investigated signals provisionally assigned as FAHFAs are in fact FA dimers formed in the LC-MS pipeline. These isobaric FA dimers differ structurally only by the presence of an olefinic bond. Furthermore, stable isotope-labeled oleic acid spiked into human serum at subphysiological concentrations showed concentration-dependent formation of a diverse repertoire of FA dimers that analytically mimicked FAHFAs. Conversely, validated FAHFA species did not form spontaneously in the LC-MS pipeline. Together, these findings underscore that FAHFAs are endogenous lipid species.  However, nonbiological FA dimers forming in the setting of high concentrations of FFAs can be misidentified as FAHFAs. Based on these results, we assembled a FA dimer database to identify nonbiological FA dimers in untargeted metabolomics datasets.     

Understanding FAHFAs: From structure to metabolic regulation

The discovery of branched fatty acid esters of hydroxy fatty acids (FAHFAs) in humans draw attention of many researches to their biological effects. Although FAHFAs were originally discovered in insects and plants, their introduction into the mammalian realm opened new horizons in bioactive lipid research. Hundreds of isomers from different families have been identified so far and their role in (patho) physiological processes is currently being explored.The family of palmitic acid esters of hydroxy stearic acids (PAHSAs), especially 5-PAHSA and 9-PAHSA regioisomers, stands out in the crowd of other FAHFAs for their anti-inflammatory and anti-diabetic effects. Beneficial effects of PAHSAs have been linked to metabolic disorders such as type 1 and type 2 diabetes, colitis, and chronic inflammation. Besides PAHSAs, a growing family of polyunsaturated FAHFAs exerts mainly immunomodulatory effects and biological roles of many other FAHFAs remain currently unknown. Therefore, FAHFAs represent unique lipid messengers capable of affecting many immunometabolic processes.The objective of this review is to summarize the knowledge concerning the diversity of FAHFAs, nomenclature, and their analysis and detection. Special attention is paid to the total syntheses of FAHFAs, optimal strategies, and to the formation of the stereocenter required for optically active molecules. Biosynthetic pathways of saturated and polyunsaturated FAHFAs in mammals and plants are reviewed together with their metabolism and degradation. Moreover, an overview of biological effects of branched FAHFAs is provided and many unanswered questions regarding FAHFAs are discussed.     

Protective effects of P2X7 receptor deletion on aging-related memory alterations

Neuroinflammation is one of the factors implicated in cognitive aging. Recent studies have shown that the P2X7 receptor (P2X7R) is a major inflammatory regulator in microglia. The present study examined the effects of deletion of P2X7R on cognitive aging. Cognitive status was examined in 5-month-old (young) and 11- to 14-month-old (middle-aged) mice with P2X7R deletion (P2X7R knockout (KO)), and in age-matched control wild type mice, using the Morris water maze task. No differences were observed between the performances of young control mice and young P2X7R KO mice in the Morris water maze task. However, middle-aged P2X7R KO mice demonstrated better performance than middle-aged control mice. No differences were observed in hippocampal interleukin-1β levels and the number of microglial cells in the cornus ammonis (CA1) region of the hippocampus during microglial activation in young and middle-aged P2X7R KO mice, and control mice. Hippocampal levels of the inhibitory form of glycogen synthase kinase-3β were lower in young control mice than in mice in the other groups. These results suggest that the inhibition of P2X7R might have beneficial effects on aging-related cognitive impairments.     

Deletion of P21-activated kinase-1 induces age-dependent increased visceral adiposity and cardiac dysfunction in female mice

It is known that there is an age-related progression in diastolic dysfunction, especially prevalent in postmenopausal women, who develop heart failure with preserved ejection fraction (HFpEF, EF?>?50%). Mechanisms and therapies are poorly understood, but there are strong correlations between obesity and HFpEF. We have tested the hypothesis that P21-activated kinase-1 (PAK1) preserves cardiac function and adipose tissue homeostasis during aging in female mice. Previous demonstrations in male mice by our lab that PAK1 activity confers cardio-protection against different stresses formed the rationale for this hypothesis. Our studies compared young (3–6 months) and middle-aged (12–15 months) female and male PAK1 knock-out mice (PAK1^?/?) and wild-type (WT) equivalent. Female WT mice exhibited increased cardiac PAK1 abundance during aging. By echocardiography, compared to young WT female mice, middle-aged WT female mice showed enlargement of the left atrium as well as thickening of posterior wall and increased left ventricular mass; however, all contraction and relaxation parameters were preserved during aging. Compared to WT controls, middle-aged PAK1^?/? female mice demonstrated worsening of cardiac function involving a greater enlargement of the left atrium, ventricular hypertrophy, and diastolic dysfunction. Moreover, with aging PAK1^?/? female mice, unlike male PAK1^?/? mice, exhibited increased adiposity with increased accumulation of visceral adipose tissue. Our data provide evidence for the significance of PAK1 signaling as an element in the preservation of cardiac function and adipose tissue homeostasis in females during aging.

     

Ionizing radiation-induced mutant frequencies increase transiently in male germ cells of older mice

Spontaneous mutant frequency in the male germline increases with age, thereby increasing the risk of siring offspring with genetic disorders. In the present study we investigated the effect of age on ionizing radiation-induced male germline mutagenesis. lacI transgenic mice were treated with ionizing radiation at 4-, 15- and 26-month-old, and mutant frequencies were determined for pachytene spermatocytes and round spermatids at 15 days or 49 days after ionizing radiation treatment. Cells collected 15 days after treatment were derivatives of irradiated differentiating spermatogenic cells while cells collected 49 days later were derivatives of spermatogonial stem cells. The results showed that (1) spontaneous mutant frequency increased in spermatogenic cells recovered from nonirradiated old mice (26-months-old), particularly in the round spermatids; (2) mutant frequencies were significantly increased in round spermatids obtained from middle-aged mice (15-months-old) and old age mice (26-months-old) at 15 and 49 days after irradiation compared to the sham-treated old mice; and (3) pachytene spermatocytes obtained from 15- or 26-month-old mice displayed a significantly increased mutant frequency at 15 days post irradiation. This study indicates that age modulates the mutagenic response to ionizing radiation in the male germline.     

Prevention of Neuromusculoskeletal Frailty in Slow-Aging Ames Dwarf Mice: Longitudinal Investigation of Interaction of Longevity Genes and Caloric Restriction

Ames dwarf (Prop1 ^df/df) mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR) has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging-associated diseases and disorders that results from studies in long-lived mammals.     

Age-related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild-type mice

We assessed baseline and KCl-stimulated glutamate release by using microdialysis in freely moving young adult (7 months) and middle-aged (17 months) transgenic mice carrying mutated human amyloid precursor protein and presenilin genes (APdE9 mice) and their wild-type littermates. In addition, we assessed the age-related development of amyloid pathology and spatial memory impaired in the water maze and changes in glutamate transporters. APdE9 mice showed gradual spatial memory impairment between 6 and 15 months of age. The stimulated glutamate release declined very robustly in 17-month-old APdE9 mice as compared to 7-month-old APdE9 mice. This age-dependent decrease in stimulated glutamate release was also evident in wild-type mice, although it was not as robust as in APdE9 mice. When compared to individual baselines, all aged wild-type mice showed 25% or greater increase in glutamate release upon KCl stimulation, but none of the aged APdE9 mice. There was an age-dependent decline in VGLUT1 levels, but not in the levels of VGLUT2, GLT-1 or synaptophysin. Astrocyte activation as measured by glial acidic fibrillary protein was increased in middle-aged APdE9 mice. Blunted pre-synaptic glutamate response may contribute to memory deficit in middle-aged APdE9 mice.     

Opposing effects on cardiac function by calorie restriction in different‐aged mice

Calorie restriction (CR) increases average and maximum lifespan and exhibits an apparent beneficial impact on age‐related diseases. Several studies have shown that CR initiated either in middle or old age could improve ischemic tolerance and rejuvenate the aging heart; however, the data are not uniform when initiated in young. The accurate time to initiate CR providing maximum benefits for cardiac remodeling and function during aging remains unclear. Thus, whether a similar degree of CR initiated in mice of different ages could exert a similar effect on myocardial protection was investigated in this study. C57BL/6 mice were subjected to a calorically restricted diet (40% less than the ad libitum diet) for 3 months initiated in 3, 12, and 19 months. It was found that CR significantly reversed the aging phenotypes of middle‐aged and old mice including cardiac remodeling (cardiomyocyte hypertrophy and cardiac fibrosis), inflammation, mitochondrial damage, telomere shortening, as well as senescence‐associated markers but accelerated in young mice. Furthermore, whole‐genome microarray demonstrated that the AMP‐activated protein kinase (AMPK)–Forkhead box subgroup ‘O’ (FOXO) pathway might be a major contributor to contrasting regulation by CR initiated in different ages; thus, increased autophagy was seen in middle‐aged and old mice but decreased in young mice. Together, the findings demonstrated promising myocardial protection by 40% CR should be initiated in middle or old age that may have vital implications for the practical nutritional regimen.     

The role of estrogen receptor-beta, in the early age-related bone gain and later age-related bone loss in female mice

The molecular and cellular mechanism of estrogen action in skeletal tissue remains unclear. The purpose of this study was to understand the role of estrogen receptor-beta, (ERbeta) on cortical and cancellous bone during growth and aging by comparing the bone phenotype of 6- and 13-month-old female mice with or without ERbeta. Groups of 11-14 wild-type (WT) controls and ERbeta knockout (BERKO) female mice were necropsied at 6 and 13 months of age. At both ages, BERKO mice did not differ significantly from WT controls in uterine weight and uterine epithelial thickness, indicating that ERbeta does not regulate the growth of uterine tissue. Femoral length increased significantly by 5.5% at 6 months of age in BERKO mice compared with WT controls. At 6 months of age, peripheral quantitative computerized tomography (pQCT) analysis of the distal femoral metaphysis (DFM) and femoral shafts showed that BERKO mice had significantly higher cortical bone content and periosteal circumference as compared with WT controls at both sites. In contrast to the findings in cortical bone, at 6 months of age, there was no difference between BERKO and WT mice in trabecular density, trabecular bone volume (TBV), or formation and resorption indices at the DFM. In 13-month-old WT mice, TBV (-41%), trabecular density (-27%) and cortical thickness decreased significantly. while marrow cavity and endocortical circumference increased significantly compared with 6-month-old WT mice. These age-related decreases in cancellous and endocortical bone did not occur in BERKO mice. At 13 months of age, BERKO mice had significantly higher total, trabecular and cortical bone, while having significantly lower bone resorption, bone formation and bone turnover in DFM compared with WT mice. These results indicate that deleting ERbeta protected against age-related bone loss in both the cancellous and endocortical compartments by decreasing bone resorption and bone turnover in aged female mice. These data demonstrate that in female mice, ERbeta plays a role in inhibiting periosteal bone formation, longitudinal and radial bone growth during the growth period, while it plays a role in stimulating bone resorption, bone turnover and bone loss on cancellous and endocortical bone surfaces during the aging process.     

Age-associated differences in cardiovascular inflammatory gene induction during endotoxic stress

Upon physiological stress, families of stress response genes are activated as natural defense mechanisms. Here, we show that induction of specific inflammatory genes is significantly dysregulated and altered in the heart of aged (24--26-month-old) versus young (4-month-old) mice experimentally challenged with a bacterial endotoxin, lipopolysaccharide (LPS, 1.5 mg/kg of body mass). Whereas the LPS-mediated induction of cardiac mRNA for tumor necrosis factor alpha or inducible nitric-oxide synthase showed no age-associated differences, the induction of interleukin-1 beta (IL-1 beta) and intracellular adhesion molecule-1 was modestly extended with aging, and the induction of IL-6 was significantly prolonged with aging. This age-associated phenomenon occurred gradually from 4 to 17 months of age and became more evident after 23 months of age. The age-associated augmentation of the cardiac IL-6 induction was also dramatic at the protein level. Immunohistochemically, the LPS-induced cardiac IL-6 was localized mainly in the microvascular walls. Aged but not young mice showed a high mortality rate during these experiments. These results demonstrate that endotoxin-mediated induction of specific inflammatory genes in cardiovascular tissues is altered with aging, which may be causally related to the increased susceptibility of aged animals to endotoxic stress.     

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

Small body size has been associated with long life span in four stocks of mutant dwarf mice, and in two varieties of dietary restriction in rodents. In this study, small body size at ages 2-24 months was shown to be a significant predictor of life span in a genetically heterogeneous mouse population derived from four common inbred mouse strains. The association was strongest for weights measured early in adult life, and somewhat weaker, though still statistically significant, at later ages. The effect was seen both in males and females, and was replicated in an independent population of the same genetic background. Body size at ages 2-4 months was correlated with levels of serum leptin in both males and females, and with levels of IGF-I and thyroid hormone in females only. A genome scan showed the presence of polymorphic alleles on chromosomes 2, 6, 7 and 15 with significant effects on body weight at 2-4 months, at 10-12 months, or at both age ranges, showing that weight gain trajectory in this stock is under complex genetic control. Because it provides the earliest known predictor of life span, body weight may be usefully included in screens for induced mutations that alter aging. The evidence that weight in 2-month-old mice is a significant predictor of life span suggests that at least some of the lethal diseases of old age can be timed by factors that influence growth rate in juvenile rodents.     

Reduced Membrane Lipids in the Cortex of Alzheimer’s Disease Transgenic Mice

Accumulating evidence suggests that the conversion of Aβ peptides to soluble, neurotoxic polymers is the key event in the development of Alzheimer’s disease (AD). Moreover, interactions between Aβ peptides and neuronal membrane lipids likely play a vital role in developing the neurotoxicity associated with AD. The aim of this study is to assess whether lipid matrix of neuronal membranes is affected by the accumulation of Aβ peptides in double transgenic mouse model of AD expressing both mutant human β-amyloid precursor protein (APP) and presenilin 1 (PS1). We apply high pressure liquid chromatography with an evaporative light scattering detector to compare levels of cholesterol, galactocerebrosides, and phospholipid subclasses simultaneously in cortex samples between AD double transgenic mice at 4 months of age when Aβ production and amyloid plaque deposition is just beginning and at 9 months, when there is advanced Aβ levels and plaque deposition compared to age-matched wild-type (B6/SJL) mice. Both cholesterol (CL) and phospholipids (PL) are significantly lower in 9-month-old AD mice than the same age of B6/SJL mice. Among PL subclasses, phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC) are selectively reduced in 9-month-old AD mice. The molar ratios of CL to PL in 9-month-old AD mice (1.19 ± 0.27) were significantly higher than those of 9-month-old B6/SJL mice (0.81 ± 0.08). In keeping with decreased levels of PL, there are also significant reductions of very long-chain n-3 fatty acids (docosahexaenoic acid) and n-6 fatty acid (arachidonic acid) in 9-month-old AD mice. On the other hand, ratios of total n-6 to total n-3 fatty acids were significantly higher in 9-month-old AD mice than in the same age of B6/SJL mice. Taken together, our present data support a role for the interactions of amyloid-β peptide and neuronal membranes in the subsequent development of AD. Special issue article in honor of Dr. George DeVries.     

Long-term dietary restriction up-regulates activity and expression of renal arginase II in aging mice

Arginase II is a mitochondrial enzyme that catalyses the hydrolysis of L-arginine into urea and ornithine. It is present in other extra-hepatic tissues that lack urea cycle. Therefore, it is plausible that arginase II has a physiological role other than urea cycle which includes polyamine, proline, glutamate synthesis and regulation of nitric oxide production. The high expression of arginase II in kidney, among extrahepatic tissues, might have an important role associated with kidney functions. The present study is aimed to determine the age-associated alteration in the activity and expression of arginase II in the kidney of mice of different ages. The effect of dietary restriction to modulate the age-dependent changes of arginase II was also studied. Results showed that renal arginase II activity declines significantly with the progression of age (p<0.01 and p<0.001 in 6- and 18-month-old mice, respectively as compared to 2-month old mice) and is due to the reduction in its protein as well as the mRNA level (p<0.001 in both 6- and 18-month-old mice as compared to 2-month-old mice). Long-term dietary restriction for three months has significantly up-regulated arginase II activity and expression level in both 2- and 18-month-old mice (p<0.01 and p<0.001, respectively as compared to AL group). These findings clearly indicate that the reducing level of arginase II during aging might have an impact on the declining renal functions. This age-dependent down-regulation of arginase II in the kidney can be attenuated by dietary restriction which may help in the maintenance of such functions.     

Role of apolipoprotein E in renal damage protection

It is well-known that nephrotic syndrome and chronic renal failure are associated with lipid and lipoprotein abnormalities. For a long time, it has been thought that hyperlipidemia is a secondary and insignificant condition of these renal injuries. Recently, it has been shown that dyslipidaemia may contribute to the development and progression of chronic kidney disease. Apolipoprotein E (apoE) null mice are a very popular model for studying spontaneous hypercholesterolemia, but only limited data are available for the role of apolipoprotein E in kidney disease. The purpose of this study is to evaluate kidney disease in apolipoprotein E deficient mice. For this study, apoE null mice and control mice at different ages (6 weeks and 15 months) were used. Kidney morphological damage and proteins involved in oxidative stress and aging (TNF-α and NF-kB) were analyzed. ApoE deficient mice have morphological alterations that are the hallmark of kidney pathogenesis, which increase with the age of the animals. In apoE null mice kidneys, there is also increased oxidative stress as compared to control mice at the same age and fewer antioxidant enzymes. Our findings add to the growing list of protective effects that apoE possesses.     

Tissue-specific and age-related variations in repetitive sequences of mouse extrachromosomal circular DNAs

Extrachromosomal circular (ecc) DNA was isolated from mouse brain, liver, and heart tissues at different ages. To determine the abundance of repetitive sequences in eccDNAs, preparations were probed for short-interspersed (B1 and B2), long-interspersed (L1), endogenous retroviral-like (IAP), and tandemly repeated satellite sequences (SAT) of the mouse genome. Together these sequence families comprise approximately 15% of the mouse genome. The hybridization results showed that each tissue had a characteristic pattern of repetitive sequence elements in eccDNAs, and the abundance of repetitive sequences changed as a function of age. Repetitive sequences decreased in liver and brain eccDNAs from 1 month to 8 months of age but appeared to remain stable thereafter. In contrast, repetitive sequence families in heart eccDNAs were constant from 1 month to 16 months of age but declined in 24-month-old mice. The present studies indicate that extrachromosomal sequences exhibit greater flexibility than chromosomal sequences.     

Quantitative Proteomic Analysis of Mitochondria in Aging PS-1 Transgenic Mice

Accumulating evidence suggests mitochondrial alterations are intimately associated with the pathogenesis of Alzheimer’s disease (AD). In order to determine if mutations of presenilin-1 (PS-1) affect levels of mitochondrial proteins at different ages we enriched mitochondrial fractions from 3-, 6-, 12-month-old knock-in mice expressing the M146V PS-1 mutation and identified, and quantified proteins using cleavable isotope-coded affinity tag labeling and two-dimensional liquid chromatography/tandem mass spectrometry (2D-LC/MS/MS). Using this approach, 165 non-redundant proteins were identified with 80 of them present in all three age groups. Specifically, at young ages (3 and 6 months), Na⁺/K⁺ ATPase and several signal transduction proteins exhibited elevated levels, but dropped dramatically at 12 months. In contrast, components of the oxidative phosporylation pathway (OXPHOS), the mitochondrial permeability transition pore (MPTP), and energy metabolism proteins remained unchanged at 3 months but significantly increased with age. We propose that alterations in calcium homeostasis induced by the PS-1 mutation have a major impact in young animals by inhibiting the function of relevant proteins and inducing compensatory changes. However, in older mice combination of the PS-1 mutation and accumulated oxidative damage results in a functional suppression of OXPHOS and MPTP proteins requiring a compensatory increase in expression levels. In contrast, signal transduction proteins showed decreased levels due to a break down in the compensatory mechanisms. The dysfunction of Na⁺/K⁺ ATPase and signal transduction proteins may induce impaired cognition and memory before neurodegeneration occurs. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

Changes in DNA methylation influence the aging process and contribute to aging phenotypes, but few studies have been conducted on DNA methylation changes in conjunction with skeletal muscle aging. We explored the DNA methylation changes in a variety of retroelement families throughout aging (at 2, 20, and 28 months of age) in murine skeletal muscles by methyl‐binding domain sequencing (MBD‐seq). The two following contrasting patterns were observed among the members of each repeat family in superaged mice: (a) hypermethylation in weakly methylated retroelement copies and (b) hypomethylation in copies with relatively stronger methylation levels, representing a pattern of “regression toward the mean” within a single retroelement family. Interestingly, these patterns depended on the sizes of the copies. While the majority of the elements showed a slight increase in methylation, the larger copies (>5 kb) displayed evident demethylation. All these changes were not observed in T cells. RNA sequencing revealed a global derepression of retroelements during the late phase of aging (between 20 and 28 months of age), which temporally coincided with retroelement demethylation. Following this methylation drift trend of “regression toward the mean,” aging tended to progressively lose the preexisting methylation differences and local patterns in the genomic regions that had been elaborately established during the early period of development.     

SIRT2 induces the checkpoint kinase BubR1 to increase lifespan

Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1^H/H) live shorter and show signs of accelerated aging. As wild‐type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age‐related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1‐7) are a family of NAD⁺‐dependent deacetylases that can delay age‐related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD⁺ and the ability of SIRT2 to maintain lysine‐668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of SIRT2 or treatment of mice with the NAD⁺ precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of SIRT2 in BubR1^H/H animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of SIRT2 and NAD⁺ to delay diseases of aging in mammals is warranted.