Cognitive profile, neuroimaging and fluid biomarkers in post-acute COVID-19 syndrome.

We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.

The effects of adaptation to urea on feeding rates and growth in Drosophila larvae.

A collection of forty populations were used to study the phenotypic adaptation of Drosophila melanogaster larvae to urea-laced food. A long-term goal of this research is to map genes responsible for these phenotypes. This mapping requires large numbers of populations. Thus, we studied fifteen populations subjected to direct selection for urea tolerance and five controls. In addition, we studied another twenty populations which had not been exposed to urea but were subjected to stress or demographic selection. In this study, we describe the differentiation in these population for six phenotypes: (1) larval feeding rates, (2) larval viability in urea-laced food, (3) larval development time in urea-laced food, (4) adult starvation times, (5) adult desiccation times, and (6) larval growth rates. No significant differences were observed for desiccation resistance. The demographically/stress-selected populations had longer times to starvation than urea-selected populations. The urea-adapted populations showed elevated survival and reduced development time in urea-laced food relative to the control and nonadapted populations. The urea-adapted populations also showed reduced larval feeding rates relative to controls. We show that there is a strong linear relationship between feeding rates and growth rates at the same larval ages feeding rates were measured. This suggests that feeding rates are correlated with food intake and growth. This relationship between larval feeding rates, food consumption, and efficiency has been postulated to involve important trade-offs that govern larval evolution in stressful environments. Our results support the idea that energy allocation is a central organizing theme in adaptive evolution.

Dietary strawberry improves cognition in a randomised, double-blind, placebo-controlled trial in older adults.

Functional changes in the brain during ageing can alter learning and memory, gait and balance - in some cases leading to early cognitive decline, disability or injurious falls among older adults. Dietary interventions with strawberry (SB) have been associated with improvements in neuronal, psychomotor and cognitive functions in rodent models of ageing. We hypothesised that dietary supplementation with SB would improve mobility and cognition among older adults. In this study, twenty-two men and fifteen women, between the ages of 60 and 75 years, were recruited into a randomised, double-blind, placebo-controlled trial in which they consumed either freeze-dried SB (24 g/d, equivalent to two cups of fresh SB) or a SB placebo for 90 d. Participants completed a battery of balance, gait and cognitive tests at baseline and again at 45 and 90 d of intervention. Significant supplement group by study visit interactions were observed on tests of learning and memory. Participants in the SB group showed significantly shorter latencies in a virtual spatial navigation task (P = 0·020, ηp2 = 0·106) and increased word recognition in the California Verbal Learning test (P = 0·014, ηp2 = 0·159) across study visits relative to controls. However, no improvement in gait or balance was observed. These findings show that the addition of SB to the diets of healthy, older adults can improve some aspects of cognition, but not gait or balance, although more studies with a larger sample size and longer follow-up are needed to confirm this finding.

Blueberry phenolics are associated with cognitive enhancement in supplemented healthy older adults.

Blueberries (BB) contain an array of bioactive phenolic compounds that may play a protective role against various age-related diseases. Here we explored the metabolic fate of BB phenolics and their relationship to cognitive function after chronic (90 days) supplementation of freeze-dried BB (24 g d-1, equivalent to 1 cup of fresh BB) or control in a randomized, double-blind, parallel study with 38 healthy older adults (60-75 years). Blood samples were collected at fasting (t = 0 h) and 2 h after a breakfast meal on days 0 (no treatment), 45, and 90, and a battery of cognitive tests was also conducted on these days. Hippuric acid, phloroglucinaldehyde, syringic acid, ferulic acid-glucuronide, cyanidin-3-O-galactoside, cyanidin-3-O-glucoside, malvidin-3-O-galactoside, malvidin-3-O-glucoside, peonidin-3-O-xyloside, peonidin glucuronide, and petunidin-3-O-glucoside concentrations were significantly altered after 90 days of BB consumption compared to control. Stepwise regression was used to assess the relationship between significantly altered concentrations of plasma phenolics and observed improvements in cognition. Among participants in the BB group, changes in switch errors on the task-switching test (TST) from day 0 to 90 were associated with changes in postprandial levels of plasma ferulic acid-glucuronide, syringic acid, and malvidin-3-galactoside (R2 = 0.521, p < 0.05). Changes in repetition errors on the California Verbal Learning Test (CVLT-II) from day 0 to 90 were associated with changes in postprandial levels of ferulic acid-glucuronide, syringic acid, and hippuric acid (R2 = 0.807, p < 0.001). These findings demonstrate that the addition of easily achievable quantities of BB to the diets of older adults significantly alters levels of circulating phenolic compounds which are related to improvements in cognition.

Diet and Botanical Supplementation: Combination Therapy for Healthspan Improvement?

Healthspan science aims to add healthy, functional years to human life. Many different methods of improving healthspan have been investigated, chiefly focusing on just one aspect of an organism's health such as survival. Studies in Drosophila melanogaster have demonstrated that a reversal to a long-abandoned ancestral diet results in improved functional health, particularly at later ages. Meanwhile, pharmaceutical studies have demonstrated that botanical extracts have potent antiaging properties, capable of extending the mean lifespan of D. melanogaster by up to 25%, without a decrease in early fecundity. In this study, we combine these two different approaches to healthspan extension to examine whether a combination of such treatments results in a synergistic or antagonistic effect on Drosophila healthspan. One botanical extract, derived from Rhodiola rosea, mimicked the effects of the ancestral apple diet with better performance at later ages compared with the control. Another extract, derived from Rosa damascena, decreased age-specific survivorship when combined with the apple diet providing support for the "Poisoned Chalice" hypothesis that combinations of various supplements or diets can elicit adverse physiological responses. More experiments in model organisms should be completed researching the effects of combining healthspan-extending substances in various diet backgrounds.

Foveal macular pigment dip in offspring of age-related macular degeneration patients is inversely associated with omega-3 index.

BACKGROUND: Offspring of parent(s) with age-related macular degeneration (AMD) have a 45% lifetime risk of developing the disease. High foveal macular pigment optical density (MPOD) is protective, whereas individuals with a "foveal macular pigment dip" (FMPD) are at increased risk. Shortage of the dietary carotenoids lutein, zeaxanthin as well as fish consumption are reported AMD risk factors. This Early Biomarkers of AMD (EBAMD) study evaluates serum factors that protect foveal MPOD architecture in Caucasian offspring of parent(s) with AMD. METHODS: N = 130 subjects [mean (SD) age 62.8 (8.6) years; 36/94 male/female] were recruited from Scripps Health/ Scripps Memorial Hospital/ Scripps Mericos Eye Institute between 2012 and 2017. Macula pigment 3D topography was evaluated using specular reflectance. Buccal genetic cheek swab, circulating serum dietary carotenoids and long-term RBC omega-3 fatty acid status, as well as common secondary clinical structural and vision function parameters were obtained. RESULTS: 41 % of offspring of AMD parent(s) presented with FMPD. These offspring were about 4 years younger than those without FMPD (controls; P = 0.012) and had thinner foveas (P = 0.010). There were no differences in gender, BMI, % body fat, visual acuity or contrast sensitivity between those with and without FMPD. % RBC membrane docosahexaenoic acid (DHA) was reduced in FMPD offspring vs. control offspring (P = 0.04). The Omega-3 Index was significantly decreased in the FMPD group (P = 0.03). CONCLUSIONS: The percentage of FMPD in AMD offspring is nearly twice that reported for the general population in the scientific literature. Offspring presenting FMPD had similar AMD genetic risk, but significantly reduced % RBC membrane omega-3 fatty acids and thinner foveas compared with those without FMPD. Our data supports the importance of 'essential fatty' acids as an independent AMD risk factor.

Hamiltonian patterns of age-dependent adaptation to novel environments.

Our intuitive understanding of adaptation by natural selection is dominated by the power of selection at early ages in large populations. Yet, as the forces of natural selection fall with adult age, we expect adaptation to be attenuated with age. Explicit simulations of age-dependent adaptation suggest that populations adapt to a novel environment quickly at early ages, but only slowly and incompletely at later adult ages. Experimental tests for age-dependent adaptation to a novel diet were performed on populations of Drosophila melanogaster. The results support the prediction that populations should perform better on an ancestral, long-abandoned diet, compared to an evolutionarily recent diet, only at later ages. D. melanogaster populations also perform poorly on a novel diet compared to an evolutionarily recent diet that has been sustained for hundreds of generations, particularly at earlier ages. Additional experiments demonstrate that the timing of the shift to better performance in our populations on the long-abandoned diet is dependent on when the forces of natural selection weaken in the evolutionary history of experimental populations. Taken together, these experimental findings suggest that the forces of natural selection scale the rate of adaptation to novel environments.

The effects of blueberry and strawberry serum metabolites on age-related oxidative and inflammatory signaling in vitro.

Berry fruits contain a variety of bioactive polyphenolic compounds that exhibit potent antioxidant and anti-inflammatory activities. We have shown that consumption of freeze-dried whole berry powder, equivalent to 1 cup per day of blueberry (BB) or 2 cups per day of strawberry (SB), can differentially improve some aspects of cognition in healthy, older adults, compared to placebo-supplemented controls. We investigated whether fasting and postprandial serum from BB- or SB-supplemented older adults (60-75 years), taken at baseline or after 45 or 90 days of supplementation, would reduce the production of inflammatory and oxidative stress markers compared to serum from a placebo group, in LPS-stressed HAPI rat microglial cells, in vitro. Serum from both BB- and SB-supplemented participants reduced nitrite production, iNOS and COX-2 expression, and TNF-alpha release relative to serum from placebo controls (p < 0.05). Protection was greatest with serum from the 90-day time-point, suggesting that ongoing supplementation may provide the most health benefits. Serum was protective in both fasted and postprandial conditions, indicating that the effects are not only acute and that the meal did not challenge subjects' ability to regulate oxidative and inflammatory stress. These results suggest that berry metabolites, present in the circulating blood following ingestion, may be mediating the anti-inflammatory effects of dietary berry fruit.

Genomics of Early Cardiac Dysfunction and Mortality in Obese Drosophila melanogaster.

In experimental evolution, we impose functional demands on laboratory populations of model organisms using selection. After enough generations of such selection, the resulting populations constitute excellent material for physiological research. An intense selection regime for increased starvation resistance was imposed on 10 large outbred Drosophila populations. We observed the selection responses of starvation and desiccation resistance, metabolic reserves, and heart robustness via electrical pacing. Furthermore, we sequenced the pooled genomes of these populations. As expected, significant increases in starvation resistance and lipid content were found in our 10 intensely selected SCO populations. The selection regime also improved desiccation resistance, water content, and glycogen content among these populations. Additionally, the average rate of cardiac arrests in our 10 obese SCO populations was double the rate of the 10 ancestral CO populations. Age-specific mortality rates were increased at early adult ages by selection. Genomic analysis revealed a large number of single nucleotide polymorphisms across the genome that changed in frequency as a result of selection. These genomic results were similar to those obtained in our laboratory from less direct selection procedures. The combination of extensive genomic and phenotypic differentiation between these 10 populations and their ancestors makes them a powerful system for the analysis of the physiological underpinnings of starvation resistance.

Effects of evolutionary history on genome wide and phenotypic convergence in Drosophila populations.

BACKGROUND: Studies combining experimental evolution and next-generation sequencing have found that adaptation in sexually reproducing populations is primarily fueled by standing genetic variation. Consequently, the response to selection is rapid and highly repeatable across replicate populations. Some studies suggest that the response to selection is highly repeatable at both the phenotypic and genomic levels, and that evolutionary history has little impact. Other studies suggest that even when the response to selection is repeatable phenotypically, evolutionary history can have significant impacts at the genomic level. Here we test two hypotheses that may explain this discrepancy. Hypothesis 1: Past intense selection reduces evolutionary repeatability at the genomic and phenotypic levels when conditions change. Hypothesis 2: Previous intense selection does not reduce evolutionary repeatability, but other evolutionary mechanisms may. We test these hypotheses using D. melanogaster populations that were subjected to 260 generations of intense selection for desiccation resistance and have since been under relaxed selection for the past 230 generations. RESULTS: We find that, with the exception of longevity and to a lesser extent fecundity, 230 generations of relaxed selection has erased the extreme phenotypic differentiation previously found. We also find no signs of genetic fixation, and only limited evidence of genetic differentiation between previously desiccation resistance selected populations and their controls. CONCLUSION: Our findings suggest that evolution in our system is highly repeatable even when populations have been previously subjected to bouts of extreme selection. We therefore conclude that evolutionary repeatability can overcome past bouts of extreme selection in Drosophila experimental evolution, provided experiments are sufficiently long and populations are not inbred.

Rapid divergence and convergence of life-history in experimentally evolved Drosophila melanogaster.

Laboratory selection experiments are alluring in their simplicity, power, and ability to inform us about how evolution works. A longstanding challenge facing evolution experiments with metazoans is that significant generational turnover takes a long time. In this work, we present data from a unique system of experimentally evolved laboratory populations of Drosophila melanogaster that have experienced three distinct life-history selection regimes. The goal of our study was to determine how quickly populations of a certain selection regime diverge phenotypically from their ancestors, and how quickly they converge with independently derived populations that share a selection regime. Our results indicate that phenotypic divergence from an ancestral population occurs rapidly, within dozens of generations, regardless of that population's evolutionary history. Similarly, populations sharing a selection treatment converge on common phenotypes in this same time frame, regardless of selection pressures those populations may have experienced in the past. These patterns of convergence and divergence emerged much faster than expected, suggesting that intermediate evolutionary history has transient effects in this system. The results we draw from this system are applicable to other experimental evolution projects, and suggest that many relevant questions can be sufficiently tested on shorter timescales than previously thought.

The great evolutionary divide: two genomic systems biologies of aging.

There is not one systems biology of aging, but two. Though aging can evolve in either sexual or asexual species when there is asymmetric reproduction, the evolutionary genetics of aging in species with frequent sexual recombination are quite different from those arising when sex is rare or absent. When recombination is rare, selection is expected to act chiefly on rare large-effect mutations, which purge genetic variation due to genome-wide hitchhiking. In such species, the systems biology of aging can focus on the effects of large-effect mutants, transgenics, and combinations of such genetic manipulations. By contrast, sexually outbreeding species maintain abundant genetic polymorphism within populations. In such species, the systems biology of aging can examine the genome-wide effects of selection and genetic drift on the numerous polymorphic loci that respond to laboratory selection for different patterns of aging. An important question of medical relevance is to what extent insights derived from the systems biology of aging in model species can be applied to human aging.

An evolutionary and genomic approach to challenges and opportunities for eliminating aging.

While solutions to major scientific and medical problems are never perfect or complete, it is still reasonable to delineate cases where both have been essentially solved. For example, Darwin's theory of natural selection provides a successful solution to the problem of biological adaptation, while the germ theory of infection solved the scientific problem of contagious disease. Likewise in the context of medicine, we have effectively solved the problem of contagious disease, reducing it to a minor cause of death and disability for almost everyone in countries with advanced medicine and adequate resources. Evolutionary biologists claim to have solved the scientific problem of aging: we explain it theoretically using Hamilton's forces of natural selection; in experimental evolution we readily manipulate the onset, rate, and eventual cessation of aging by manipulating these forces. In this article, we turn to the technological challenge of solving the medical problem of aging. While we feel that the broad outlines of such a solution are clear enough starting from the evolutionary solution to the scientific problem of aging, we do not claim that we can give a complete or exhaustive plan for medically solving the problem of aging. But we are confident that biology and medicine will effectively solve the problem of aging within the next 50 years, providing Hamiltonian lifestyle changes, tissue repair, and genomic technological opportunities are fully exploited in public health practices, in medical practice, and in medical research, respectively.