Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

First-in-human liver transplantation from a centenarian deceased donor after brain death.

Liver transplantation from elderly donors is expanding due to demand for liver grafts, aging of recipients and donors, and introduction of machine perfusion. We report on a liver transplant from a 100-year-old deceased donor after brain death. The liver was transplanted after the use of hypothermic machine perfusion to a 60-year-old recipient with advanced hepatocellular carcinoma undergoing neoadjuvant immunotherapy. Nine months after the transplant, the patient is alive with a functioning graft and no evidence of acute rejection or tumor recurrence.

Sicilian semi- and supercentenarians: age-related Tγδ cell immunophenotype contributes to longevity trait definition.

The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e. oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1, and Vδ2, and their functional subsets using the markers defining Tαß cells, i.e. CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (from >90 years old to<105 years old), and eight oldest centenarians (≥105 years old), all of them were previously analysed for Tαß and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in the oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαß cell values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity.

Sicilian semi- and supercentenarians: identification of age-related T-cell immunophenotype to define longevity trait.

The immunophenotype of oldest centenarians, i.e. semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19-110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest percentages of T-effector memory cells re-expressing CD45RA (TEMRA), according to their cytomegalovirus status, and high levels of serum pro-inflammatory parameters, although their means were lower than that of remaining 90+ donors. Some of them showed CD8 naïve and TEMRA percentages, and exhaustion/pro-inflammatory markers comparable to the younger ones. Our study supports the suggestion that immune ageing, especially of oldest centenarians, exhibits great variability that is not only attributable to a single contributor but should also be the full result of a combination of several factors. Everyone ages differently because he/she is unique in genetics and experience of life and this applies even more to the immune system; everybody has had a different immunological history. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians, discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and in particular for the oldest ones.

The Independent Impact of Peripheral Arterial Disease on Mortality in Nonagenarians and Centenarians Who Were Treated in an Intensive Care Unit: A Consecutive Cohort of 1 108 Patients.

OBJECTIVE: To investigate the clinical characteristics, risk factors, and outcomes of inpatients with peripheral arterial disease (PAD) including lower extremity PAD, abdominal aortic aneurysm (AAA), and carotid artery disease in a large cohort of critically ill patients aged ≥ 90 years. METHODS: A retrospective analysis was conducted of all adult patients aged ≥ 90 years consecutively admitted to the intensive care unit at a tertiary care centre in Hamburg, Germany, between 1 January 2008 and 30 April 2019. Multivariable regression and Kaplan-Meier methods were used to determine the independent impact of PAD on short and long term mortality endpoints. The analyses were adjusted for confounding by several sociodemographic and clinical parameters including Charlson Comorbidity Index (CCI) and established clinical risk scores. RESULTS: A total of 1 108 eligible patients were identified (92.3 years, 33% men). Of these, 24% had PAD (9% lower extremity PAD, 2% AAA, 15% coronary artery disease) and 76% did not have any history of PAD and were used as a comparison group. When compared with the comparison group, patients with PAD had a higher CCI (2 vs. 1, p < .001), more often had chronic kidney disease (28% vs. 21%, p = .019), and renal replacement therapy (5% vs. 2%, p = .016). Furthermore, they needed vasopressors (48% vs. 40%, p = .027) and parenteral nutrition (10% vs. 6%, p = .041) more often. After adjusting for confounding, PAD was independently associated with increased in hospital (hazard ratio [HR] 1.97, 95% confidence interval [CI] 1.39 - 2.81, p < .001) and long term mortality rates (HR 1.32, 95% CI 1.05 - 1.66, p = .019). CONCLUSION: One of four critically ill nonagenarians and centenarians in an ICU in Germany had PAD. PAD was associated with both higher short and long term mortality rates while its impact outweighed higher age. Future studies should address this increasingly important population beyond 89 years of age.

The relationship between depressive mood and subjective health in centenarians and near-centenarians: a cross-sectional study from Korean centenarian cohort.

BACKGROUND: With the rapid increase in population longevity, more clinical attention is being paid to the overall health of long-lived people, especially centenarians. Subjective health, which is the perception of one's health status, predicts both mortality and declining physical function in older adults. The purpose of this study was to investigate the factors related to subjective health among centenarians and near-centenarians (ages ≥95) living in a rural area of South Korea. METHODS: A total of 101 participants were enrolled from four different regions (Gurye, Gokseong, Sunchang, and Damyang), known as the Longevity Belt in Korea. Variables assessing physical and mental health, including the results of blood tests, were examined. Factors associated with good subjective health were identified with logistic regression analysis. RESULTS: Fifty-six participants (59.6%) were subjectively healthy among the centenarians and near-centenarians. Logistic regression analysis revealed that depressive mood was the only factor associated with subjective health and was negatively correlated. The regression model explained 39% of the variance in subjective health. CONCLUSIONS: These findings emphasize the importance of mental health at very advanced ages. Because depressive mood negatively correlates with subjective health, more attention is needed to prevent and manage mood symptoms of people of advanced ages, including centenarians.

Coping Patterns in Advanced Old Age: Findings from the Fordham Centenarian Study.

INTRODUCTION: Research on coping in advanced old age is scarce. In the present study, we explored coping patterns in near-centenarians and centenarians, and characteristics associated to using a specific coping pattern. METHODS: We analyzed the frequency with which participants (N = 87, MAge = 99.05; SDage = 2.6; age range 95-107) reported using specific coping strategies (i.e., coping strategy use) and the relative preference for specific strategies (i.e., relative coping preferences) in data from the Fordham Centenarian Study. Moreover, we applied cluster analysis to detect coping patterns, and we compared cluster characteristics. RESULTS: Very old individuals reported using emotion control and acceptance the most. Cluster analysis further revealed two distinct groups: The high coping group reported significantly higher coping strategy use than the low coping group (p < 0.001). The two groups also favored different strategies (p < 0.001), with the high coping group showing significantly higher relative preferences than the low coping group for active problem-solving, proactive prevention, and strategic planning (all ps < 0.05). The groups furthermore differed significantly in psychological strengths (i.e., personality, self-efficacy, ps < 0.001) and well-being outcomes (i.e., life satisfaction, p = 0.05). DISCUSSION: This study provides evidence for a general preference for acceptance and emotion control in very old individuals, supporting theories of a developmental coping shift in old age, yet our findings also document the existence of groups with different coping patterns. More frequent coping use, and particularly continued use of active problem-solving and proactive prevention, may enable well-being in very old age.

Association among Terminally Differentiated T Cells, Frailty, and Dependency in a Group of Cuban Centenarians.

INTRODUCTION: Centenarians are considered a model of successful aging. Cuba exhibits one of the oldest populations in Latin America with more than two thousand centenarians. METHODS: This study aimed to evaluate the immune phenotype of forty-three Cuban centenarians, their clinical characteristics such as comorbidities, frailty, body mass index, and some hemochemical parameters. RESULTS: Centenarians had normal body mass indexes, relatively good health status, and 21.95% of them had no comorbidities; 53.6% were classified as frail, and 7% were classified as robust. In addition, 17% of centenarians were independent, and 41.46% were moderately dependent. The seroprevalence against cytomegalovirus was 100%. Concerning pro-inflammatory markers, the majority of them had very low cytokine levels and serum C-reactive protein around the normal limit. We also found the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells. Terminally differentiated CD8+CD28- T cells were higher in frail centenarians than in pre-frail, while CD8+CD57+ and CD8+EMRA T cells were higher in moderately and severely dependent individuals than in independent individuals. Severely dependent centenarians had a lower CD4+/CD8+ ratio. CONCLUSION: This study describes for the first time the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells, as well as its relation to frailty and/or dependency in a group of Cuban centenarians. Further studies are needed to continue understanding the natural biological aging mechanism and the relationship between terminally differentiated lymphocytes and inflammaging in the context of extreme longevity.

The relationship between sleep status and activity of daily living: based on China Hainan centenarians cohort study.

OBJECTIVE: This study, based on the China Hainan Centenarians Cohort Study (CHCCS), aims to comprehensively describe the characteristic of daytime, night and total sleep duration, sleep quality and different sleep mode of Hainan centenarians and their associations with activity of daily living (ADL) functions. METHOD: The baseline data of CHCCS was used. ADL function was evaluated the Bathel index, sleep quality was evaluated by Pittsburgh sleep quality index (PSQI), sleep status including daytime, night and total sleep duration as well as sleep quality and sleep mode. Multivariate logistic regression model was used to explore the association between sleep status and ADL disability and ADL moderate & severe disability. RESULTS: A total of 994 centenarians were included in this study with the age range 100-116 years old. Compared with the centenarians who sleep 6-9 h at night and < 2 h in the daytime, the adjusted OR between sleep > 9 h at night and sleep ≥ 2 h in the daytime and ADL disability was 2.93 (95% CI: 1.02-8.44), and adjusted OR of ADL moderate & severe disability was 2.75 (95% CI: 1.56-4.83). Compared with centenarians who sleep for 7-9 h and have good sleep quality, centenarians who sleep for > 9 h and have poor sleep quality have an increased risk of ADL moderate & severe disability (OR = 3.72, 95% CI: 1.54-9.00). CONCLUSION: Relation between sleep duration and ADL disability was more significant compared with sleep quality in Hainan centenarians. Poor sleep quality can aggravate the relationship between sleep duration and ADL moderate & severe disability.

Severe cerebrovascular pathology of the first supercentenarian to be autopsied in the world.

We report on a 116-year-old Japanese woman who was the first officially documented supercentenarian to be autopsied in the world. She lived a remarkably healthy life until suffering cerebral infarction at 109 years of age. She became Japan's oldest person at 113 years and died in 1995 from colon cancer at 116 years 175 days. Her medical records show the delayed onset of stroke, cancer, dementia, and heart disease and the importance of appropriate medical treatment and intensive dedicated care provided during the last stage of her life. She was the longest-lived person in Japan for 21 years from 1993 until 2014. The neuropathological findings of her autopsied brain were briefly reported in the Japanese literature in 1997. In this study, we reinvestigated her brain and spinal cord in more detail. Severe cerebrovascular lesions and cervical spondylotic myelopathy were found to be the main causes of her disability. Although the density of senile plaques was relatively high, the distribution of neurofibrillary tangles was limited. Ghost tangles and argyrophilic grains were mild. The mildness of tau pathological changes in her neurons, in other words the resistance of neurons to tau pathology, may be a factor responsible for her longevity.

Centenarians: who are they? A description of the total Swedish centenarian population in terms of living arrangements, health, and care utilization.

BACKGROUND: The global centenarian population has doubled each decade and is expected to continue growing. However, information regarding how they live, their health status, and care needs is limited. AIMS: This study aims to describe the total Swedish centenarian population in terms of health status, living arrangements, and socio-demographic characteristics. METHODS: This nationwide register-based study included all Swedish people reaching age 100 between 2013 and 2018. We analyzed their socio-demographic characteristics, living arrangements, number of prescribed drugs, and health status. Moreover, their care transitions from age 100 and two years forward were described. RESULTS: Of 5,882 centenarians (80.7% women), only 15.0% lived at home without formal care and 24.5% cohabited on their 100th birthday. Men (22.7%) were more likely than women (13.2%) to live at home without care. Approximately half of the centenarians lived in care homes, with fewer men (41.0%) than women (54.0%). Around 66.6% had a child living within the 50 km range. Most (76.5%) had an income below the median for Swedish older adults. Almost none were free from drugs, and polypharmacy was common (65.3%). Over half had at least one morbidity. Two years later, only 4.3% lived at home without care, and 63.9% died. CONCLUSION: Sweden's centenarian population is highly dependent on home care and care homes. Among the ones still living at home, the vast majority live alone and have low incomes. Strategies to manage health and social care demands of this growing population group in the coming decade are important.

Use of bioelectrical impedance analysis in centenarians: a systematic review.

BACKGROUND: Centenarians often represent one of the best examples of aging successfully. However, the role of body composition or hydration status assessed with bioelectrical impedance analysis (BIA) is poorly explored in this population. Therefore, the aim of this systematic review was to better understand the use and the role of BIA for evaluating body composition and hydration status in centenarians. METHODS: We conducted a systematic review of the literature up to the 1st of May, 2022 for published articles providing data on BIA to evaluate body composition parameters or hydration status in centenarians. Data were summarized descriptively because a meta-analysis was not possible due to the scarcity of available studies. RESULTS: Among 2222 articles screened, four were eligible including 291 centenarians (mean age: 100.5 years) who were mainly women (88%). In one study, BIA overestimated fat-free mass and underestimated fat mass when compared to deuterium oxide dilution. Another study carried out in Italy including 14 centenarians found a significant correlation between BIA and fat-free mass evaluated using anthropometric tools. In one study, BIA showed a significant agreement with anthropometric measures of fat mass. In the same sample, sarcopenia and dehydration, evaluated with BIA, had a high prevalence. CONCLUSION: BIA may be used for assessing body composition in centenarians, but research is limited to a few studies suggesting the need of future research in this area.

Immunosenescence and inflammatory markers in Cuban centenarians: implications for survival.

Centenarians are the best example of successful aging in humans. This work aimed to understand if immune status is associated with survival in Cuban centenarians. In a previous study, our group enrolled 43 centenarians and evaluated their immune status and functional capacity. 41 out of 43 recruited centenarians received follow-up phone calls, during a period of 2 years. Absolute CD4 + T cell count was higher among survivors, while the frequency of CD8 + CCR7-CD45RA + , CD8 + CD45RA + CD28-, and CD4 + CD28- T cells was higher among non-survivors. We also found that higher frequencies of terminally differentiated T cells were related to a higher risk of death, while centenarians with higher frequencies of T cells were more likely to survive. Surprisingly, neither serum inflammatory markers nor frailty/dependency was associated with survival. Our preliminary study suggests that immuno-senescence markers, but not inflammaging or functional capacity, are associated with survival beyond 100 years in a small group of Cuban centenarians.

Centenarians born before 1919 are resistant to COVID-19.

Although mortality from COVID-19 progressively increases with age, there are controversial data in the literature on the probability of centenarians dying from COVID-19. Moreover, it has been claimed that men in their 90s and 100s are more resilient than women. To gain insight into this matter, we analysed, according to gender, mortality data during the first year of pandemic of Sicilian nonagenarians and centenarians. We used mortality data from the 2019 as a control. The crude excess mortality between the two years was calculated. Data on deaths of Sicilian 90 + years show that, in line with what is known about the different response to infections between the two genders, oldest females are more resilient to COVID-19 than males. Moreover, centenarians born before 1919, but not "younger centenarians", are resilient to COVID-19. This latter datum should be related to the 1918 Spanish flu epidemic, although the mechanisms involved are not clear.

The bidirectional relationship between depressive symptoms and functional limitations among centenarian survivors in their 80s: Testing bivariate latent change score models.

OBJECTIVES: The purpose of the study was to examine a bivariate latent change score model of depressive symptoms and functional limitations (activities of daily living) among centenarian or near-centenarian survivors over four waves using the Health and Retirement Study. METHOD: Four hundred and sixty participants who eventually survived to age 98 or older were included by calculating their death age. Data from the time when the participants were in their 80s were analyzed. The mean age at baseline (1994) was 85.5 years. The observation interval was 2 years, from 1994 to 2000. Including age, gender, and education as a covariate, eight different models were conducted to examine the bivariate effects among depressive symptoms and functional limitations. RESULTS: Of the eight models, the bivariate model of depressive symptoms predicting change in functional limitations fitted the data best. The parameter estimates of the final model indicated significant predictive pathways from depressive symptoms to subsequent changes in depressive symptoms and functional limitations. CONCLUSION: This study tested the bidirectional relationship between depressive symptoms and functional limitations among centenarian survivors in their 80s, which uncovered that depressive symptoms is a dominant variable among the two constructs. Our findings add to a lacking number of longitudinal studies with oldest old adults.

Cognitive Reserve and Cognitive Functioning among Oldest Old Adults: Findings from the Georgia Centenarian Study.

OBJECTIVES: Living a long life does not guarantee the maintenance of optimal cognitive functioning; however, similar to older adults in general, cognitive reserve may also protect oldest-old adults from cognitive decline. The purpose of this study was to assess cognitive reserve among centenarians and octogenarians and to evaluate a process model of cognitive reserve. METHODS: A total of 321 centenarians and octogenarians from the Georgia Centenarian Study were included in this study. Cognitive reserve components included level of education, occupational responsibility, current social engagement, past engaged lifestyle, and activity. Cognitive functioning was measured with the Mini-Mental Status Examination. RESULTS: Structural equation modeling was computed, and the overall model fit well, χ2 (df = 3) = 5.02, p = .17; CFI = .99, RMSEA = .05. Education is directly and indirectly related to cognitive functioning through occupational responsibility and past engaged lifestyle. Current social engagement is related to cognitive functioning directly and indirectly through current activities. The four direct predictors (i.e., education, current social engagement, current activity, and past engaged lifestyle) explained 35% of the variance in cognitive functioning. CONCLUSION: The results provide important information for cognitive reserve theories with implications for interventions that build cognitive reserve.

Cognition, function, and prevalent dementia in centenarians and near-centenarians: An individual participant data (IPD) meta-analysis of 18 studies.

INTRODUCTION: There are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. METHODS: Participant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. RESULTS: The mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). DISCUSSION: Among the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

Study of neuropathological changes and dementia in 100 centenarians in The 90+ Study.

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age-continuous perspective.

INTRODUCTION: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals-are they resilient, or resistant to AD-associated neuropathologies? METHODS: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years. RESULTS: With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16). DISCUSSION: Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates. HIGHLIGHTS: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.