Detecting user experience issues from mHealth apps that support stroke caregiver needs: an analysis of user reviews.

Background: Existing research has demonstrated the potential of mHealth apps in improving the caregiving outcomes of stroke. Since most of the apps were published in commercially available app stores without explaining their design and evaluation processes, it is necessary to identify the user experience issues to promote long-term adherence and usage. Objective: The purpose of this study was to utilize published user reviews of commercially available apps to determine the user experience issues to guide future app development in stroke caregiving. Methods: User reviews were extracted from the previously identified 46 apps that support stroke caregiving needs using a python-scraper. The reviews were pre-processed and filtered using python scripts to consider English reviews that described issues faced by the user. The final corpus was categorized based on TF-IDF vectorization and k-means clustering technique, and the issues extracted from the various topics were classified based on the seven dimensions of user experience to highlight factors that may affect the usage of the app. Results: A total of 117,364 were extracted from the two app stores. After filtration, 13,368 reviews were included and classified based on the user experience dimensions. Findings highlight critical issues that affect the usability, usefulness, desirability, findability, accessibility, credibility, and value of the app that contribute to decreased satisfaction and increased frustration. Conclusion: The study identified several user experience issues due to the inability of the app developers to understand the needs of the user. Further, the study describes the inclusion of a participatory design approach to promote an improved understanding of user needs; therefore, limiting any issues and ensuring continued use.

Information, involvement, self-care and support-The needs of caregivers of people with stroke: A grounded theory approach.

BACKGROUND: Globally, stroke is a leading cause of death and disability, with most care undertaken by caregivers who are generally family and friends without prior experience of care. The lack of experience or unpreparedness results in feelings of uncertainty, burnout, anxiety, burden, etc. Hence, it is necessary to identify the needs of caregivers to better support them in their caregiving journey and improve the quality of care delivered. METHODS: The study employed a grounded theory methodology that utilizes information gathered from literature reviews and social media to represent the needs and create a storyline visually. The storyline is further refined and evaluated using an online survey of 72 participants recruited through online stroke caregiving communities. RESULTS: The study identified four core categories of needs: (i) Information: sufficient information delivered in layman's terms based on the individual situation of the caregiver and survivor through oral and hands-on demonstrations, (ii) Involvement: inclusion in the decision-making processes at different stages of recovery through face-to-face communication at the hospital, (iii) Self-care: ability to engage in work and leisure activities, (iv) Support: receive support in the form of resources, services and finances from different other stakeholders. CONCLUSIONS: There is a need to create a caregiver-centered approach in stroke recovery to ensure limited obstruction to care and reduced uncertainty in stroke recovery. Moreover, through the inclusion of caregivers in stroke recovery, it may be possible to reduce the burden of care to the caregiver and ensure the satisfaction of the healthcare system throughout stroke recovery.

The DNA repair enzyme, aprataxin, plays a role in innate immune signaling.

Ataxia with oculomotor apraxia type 1 (AOA1) is a progressive neurodegenerative disorder characterized by a gradual loss of coordination of hand movements, speech, and eye movements. AOA1 is caused by an inactivation mutation in the APTX gene. APTX resolves abortive DNA ligation intermediates. APTX deficiency may lead to the accumulation of 5'-AMP termini, especially in the mitochondrial genome. The consequences of APTX deficiency includes impaired mitochondrial function, increased DNA single-strand breaks, elevated reactive oxygen species production, and altered mitochondrial morphology. All of these processes can cause misplacement of nuclear and mitochondrial DNA, which can activate innate immune sensors to elicit an inflammatory response. This study explores the impact of APTX knockout in microglial cells, the immune cells of the brain. RNA-seq analysis revealed significant differences in the transcriptomes of wild-type and APTX knockout cells, especially in response to viral infections and innate immune pathways. Specifically, genes and proteins involved in the cGAS-STING and RIG-I/MAVS pathways were downregulated in APTX knockout cells, which suggests an impaired immune response to cytosolic DNA and RNA. The clinical relevance of these findings was supported by analyzing publicly available RNA-seq data from AOA1 patient cell lines. Comparisons between APTX-deficient patient cells and healthy control cells also revealed altered immune responses and dysregulated DNA- and RNA-sensing pathways in the patient cells. Overall, this study highlights the critical role of APTX in regulating innate immunity, particularly in DNA- and RNA-sensing pathways. Our findings contribute to a better understanding of the underlying molecular mechanisms of AOA1 pathology and highlights potential therapeutic targets for this disease.

mHealth intervention for carers of individuals with a history of stroke: Heuristic evaluation and user perspectives.

Background: Caregiving in stroke is complex, with most carers having little to no preparation to care for individuals with a history of stroke, leading to emotional impact. Technologies such as Mobile Health can provide the carer with real-time support and prepare the carer to assume their new roles and responsibilities. Objectives: To perform a heuristic evaluation of mHealth interventions designed to support carers of individuals with a history of stroke and determine the user preferences in stroke caregiving technology to inform future researchers and developers regarding the best practices to support these individuals. Methods: Twenty adults (i.e. 10 usability experts and 10 carers) participated in an iterative user-centred design study that focused on developing and modifying the mHealth intervention (StrokeCaregiver (SeCr)) created to support stroke caregiving. The intervention was repeated in four cycles, including two cycles with five usability experts each and five carers each. Results: SeCr was iteratively improved to develop a highly usable product in multiple cycles. Participants demonstrated critical needs in personalized information support, communication with their healthcare needs, and the trust of the user, content, and developer. These critical needs are required to be met to promote long-term acceptance and adherence. Conclusions: While SeCr was developed to address the needs of carers of individuals with a history of stroke, several considerations must be made to ensure it can be used in a real-world setting. Researchers and developers can use co-design or living lab approaches to further meet the needs and expectations of the carer and enable these individuals to be better prepared for stroke caregiving.

Utilization of social media communities for caregiver information support in stroke recovery: An analysis of content and interactions.

BACKGROUND: Caregivers often use the internet to access information related to stroke care to improve preparedness, thereby reducing uncertainty and enhancing the quality of care. METHOD: Social media communities used by caregivers of people affected by stroke were identified using popular keywords searched for using Google. Communities were filtered based on their ability to provide support to caregivers. Data from the included communities were extracted and analysed to determine the content and level of interaction. RESULTS: There was a significant rise in the use of social media by caregivers of people affected by stroke. The most popular social media communities were charitable and governmental organizations with the highest user interaction-this was for topics related to stroke prevention, signs and symptoms, and caregiver self-care delivered through video-based resources. CONCLUSION: Findings show the ability of social media to support stroke caregiver needs and practices that should be considered to increase their interaction and support.

Technology-based support for stroke caregiving: A rapid review of evidence.

AIM: This rapid review examines the technology-based interventions for caregivers of stroke proposed in the literature while also identifying the acceptance, effectiveness and satisfaction of the implemented approaches. BACKGROUND: The increasing burden of supporting stroke survivors has resulted in caregivers searching for innovative solutions, such as technology-based interventions, to provide better care. Hence, its potential to support caregivers throughout the disease trajectory needs to be assessed. EVALUATION: Five electronic databases were systematically searched for articles related to stroke caregiving technologies based on well-defined inclusion and exclusion criteria. KEY ISSUE(S): Fifteen articles met the inclusion criteria that focused on supporting caregivers through functionalities such as education, therapy and support, remote consultations, health assessments and logs and reminders using different devices. The majority of interventions demonstrated positive conclusions for caregiving impact, acceptance, effectiveness and satisfaction. CONCLUSION: Findings highlight the influences of technology in improving stroke caregiving and the need to include user-centred design principles to create a meaningful, actionable and feasible system for caregivers. IMPLICATIONS FOR NURSING MANAGEMENT: Technology can educate and support stroke caregivers, thereby minimizing uncertainty and ensuring better care for the survivor.

Caregiver Engagement in Stroke Care: Opportunities and Challenges in Australia and Denmark.

Globally, there is a rise in incident cases of stroke, particularly in low- and middle-income countries, due to obesity-related and lifestyle risk factors, including health issues such as high cholesterol, diabetes and hypertension. Since the early 20th century, stroke mortality has declined due to proper management of the risk factors and improved treatment practices. However, despite the decline in mortality, there is an increase in the levels of disability that requires long-term support. In countries such as Australia and Denmark, where most care is provided within the community; family members, generally spouses, assume the role of caregiver, with little to no preparation that affects the quality of care provided to the person living with stroke. While past research has highlighted aspects to improve caregiver preparedness of stroke and its impact on care; health planning, recovery, and public health policies rarely consider these factors, reducing engagement and increasing uncertainty. Hence, there is a need to focus on improving strategies during recovery to promote caregiver engagement. In this study, we, therefore, try to understand the needs of the caregiver in stroke that limit engagement, and processes employed in countries such as Australia and Denmark to provide care for the person with stroke. Based on our understanding of these factors, we highlight the potential opportunities and challenges to promote caregiving engagement in these countries.

Understanding the Methodological Issues and Solutions in the Research Design of Stroke Caregiving Technology.

The rise in the number of cases of stroke has resulted in a significant burden on the healthcare system. As a result, the majority of care for the person living with stroke occurs within the community, resulting in caregivers being a central and challenged agent in care. To better support caregivers during the recovery trajectory poststroke, we investigated the role of health technologies to promote education and offer various kinds of support. However, the introduction of any new technology comes with challenges due to the growing need for more user-centric systems. The integration of user-centric systems in stroke caregiving has the potential to ensure long-term acceptance, success, and engagement with the technology, thereby ensuring better care for the person living with stroke. We first briefly characterize the affordances of available technologies for stroke caregiving. We then discuss key methodological issues related to the acceptance to such technologies. Finally, we suggest user-centered design strategies for mitigating such challenges.

Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes.

Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.

mHealth applications to support caregiver needs and engagement during stroke recovery: A content review.

Caregiving in stroke results in severe physical, psychological, and social impacts on the caregiver. Over the past few years, researchers have explored the use of mHealth technologies to support healthcare-related activities due to their ability to provide real-time care at any given place or time. The purpose of this content review is to investigate mHealth apps in supporting stroke caregiving engagement based on three aspects: motivation, value, and satisfaction. We searched app stores and repositories for apps related to stroke caregiving published up to September 2020. Extracted apps were reviewed and filtered using inclusion criteria, and then downloaded onto compatible devices to determine eligibility. Results were compared with evidence-based frameworks to identify the ability of these apps in engaging and supporting the caregiver. Forty-seven apps were included in this review that enabled caregivers to support their needs, such as adjustment to new roles and relationships, involvement in care and caring for oneself using several different functionalities. These functionalities include information resources, risk assessment, remote monitoring, data sharing, reminders and so on. However, no single app was identified that focuses on all aspects of stroke caregiving. We also identified several challenges faced by users through their reviews and the factors associated with value and satisfaction. Our findings can add to the knowledge of existing mHealth technologies and their functionalities to support stroke caregiving needs, and the importance of considering user engagement in the design. They can be used by developers and researchers looking to design better mHealth apps for stroke caregiving.

The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications.

Nicotinamide adenine dinucleotide (NAD+) is an important natural molecule involved in fundamental biological processes, including the TCA cycle, OXPHOS, ß-oxidation, and is a co-factor for proteins promoting healthy longevity. NAD+ depletion is associated with the hallmarks of ageing and may contribute to a wide range of age-related diseases including metabolic disorders, cancer, and neurodegenerative diseases. One of the central pathways by which NAD+ promotes healthy ageing is through regulation of mitochondrial homeostasis via mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy. Here, we highlight the contribution of the NAD+-mitophagy axis to ageing and age-related diseases, and evaluate how boosting NAD+ levels may emerge as a promising therapeutic strategy to counter ageing as well as neurodegenerative diseases including Alzheimer's disease. The potential use of artificial intelligence to understand the roles and molecular mechanisms of the NAD+-mitophagy axis in ageing is discussed, including possible applications in drug target identification and validation, compound screening and lead compound discovery, biomarker development, as well as efficacy and safety assessment. Advances in our understanding of the molecular and cellular roles of NAD+ in mitophagy will lead to novel approaches for facilitating healthy mitochondrial homoeostasis that may serve as a promising therapeutic strategy to counter ageing-associated pathologies and/or accelerated ageing.

A functional assay-based procedure to classify mismatch repair gene variants in Lynch syndrome.

PURPOSE: To enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity (CIMRA) assay. Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data. METHODS: Two sets of previously classified MLH1 and MSH2 variants were selected from a curated MMR gene database, and their biochemical activity determined by the CIMRA assay. The assay was calibrated by regression analysis followed by symmetric cross-validation and Bayesian integration with in silico predictions of pathogenicity. CIMRA assay reproducibility was assessed in four laboratories. RESULTS: Concordance between the training runs met our prespecified validation criterion. The CIMRA assay alone correctly classified 65% of variants, with only 3% discordant classification. Bayesian integration with in silico predictions of pathogenicity increased the proportion of correctly classified variants to 87%, without changing the discordance rate. Interlaboratory results were highly reproducible. CONCLUSION: The CIMRA assay accurately predicts pathogenic and benign MMR gene variants. Quantitative combination of assay results with in silico analysis correctly classified the majority of variants. Using this calibration, CIMRA assay results can be integrated into the diagnostic algorithm for MMR gene variants.

The inhibitors of soluble adenylate cyclase 2-OHE, KH7, and bithionol compromise mitochondrial ATP production by distinct mechanisms.

Soluble adenylate cyclase (sAC) is a non-plasma membrane-bound isoform of the adenylate cyclases signaling via the canonical second messenger, 3',5'-cyclic AMP (cAMP). sAC is involved in key physiological processes such as insulin release, sperm motility, and energy metabolism. Thus, sAC has attracted interest as a putative drug target and attempts have been made to develop selective inhibitors. Since sAC has a binding constant for its substrate, ATP, in the millimolar range, reductions in mitochondrial ATP production may be part of the mechanism-of-action of sAC inhibitors and the potential of these compounds to study the physiological outcomes of inhibition of sAC might be severely hampered by this. Here, we evaluate the effects of two commonly employed inhibitors, 2-OHE and KH7, on mitochondrial ATP production and energy metabolism. For comparison, we included a recently identified inhibitor of sAC, bithionol. Employing mitochondria isolated from mouse brain, we show that all three compounds are able to curb ATP production albeit via distinct mechanisms. Bithionol and KH7 mainly inhibit ATP production by working as a classical uncoupler whereas 2-OHE mainly works by decreasing mitochondrial respiration. These findings were corroborated by investigating energy metabolism in acute brain slices from mice. Since all three sAC inhibitors are shown to curb mitochondrial ATP production and affect energy metabolism, caution should be exercised when employed to study the physiological roles of sAC or for validating sAC as a drug target.

Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.

Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

A Novel Rrm3 Function in Restricting DNA Replication via an Orc5-Binding Domain Is Genetically Separable from Rrm3 Function as an ATPase/Helicase in Facilitating Fork Progression.

In response to replication stress cells activate the intra-S checkpoint, induce DNA repair pathways, increase nucleotide levels, and inhibit origin firing. Here, we report that Rrm3 associates with a subset of replication origins and controls DNA synthesis during replication stress. The N-terminal domain required for control of DNA synthesis maps to residues 186-212 that are also critical for binding Orc5 of the origin recognition complex. Deletion of this domain is lethal to cells lacking the replication checkpoint mediator Mrc1 and leads to mutations upon exposure to the replication stressor hydroxyurea. This novel Rrm3 function is independent of its established role as an ATPase/helicase in facilitating replication fork progression through polymerase blocking obstacles. Using quantitative mass spectrometry and genetic analyses, we find that the homologous recombination factor Rdh54 and Rad5-dependent error-free DNA damage bypass act as independent mechanisms on DNA lesions that arise when Rrm3 catalytic activity is disrupted whereas these mechanisms are dispensable for DNA damage tolerance when the replication function is disrupted, indicating that the DNA lesions generated by the loss of each Rrm3 function are distinct. Although both lesion types activate the DNA-damage checkpoint, we find that the resultant increase in nucleotide levels is not sufficient for continued DNA synthesis under replication stress. Together, our findings suggest a role of Rrm3, via its Orc5-binding domain, in restricting DNA synthesis that is genetically and physically separable from its established catalytic role in facilitating fork progression through replication blocks.

Acquired Localized Cutis Laxa due to Increased Elastin Turnover.

Cutis laxa is a rare disease characterized by abnormal skin wrinkling and laxity, due to decreased elastin synthesis or structural extracellular matrix defects. We have explored elastin metabolism in a case of adult onset cutis laxa localized to the upper body of a woman. For this purpose, we obtained skin biopsies from affected and unaffected skin areas of the patient and analyzed these with microscopy, polymerase chain reaction, western blotting and cell culture experiments. Skin from the affected area lacked elastin fibers in electron microscopy but had higher mRNA expression of elastin and total RNA. Levels of an apparent tropoelastin degradation product were higher in the affected area. Fibroblast cultures from the affected area were able to produce elastin and showed higher proliferation and survival after oxidative and UVB stress compared to fibroblasts from the unaffected area. In conclusion, we report a case of acquired localized cutis laxa with a lack of elastic fibers in the skin of the patient's upper body. The lack of elastic fibers in the affected skin was combined with increased mRNA expression and protein levels of elastin. These findings indicate that elastin synthesis was increased but did not lead to deposited elastic fibers in the tissue.

Oxidative Stress-Induced Dysfunction of Müller Cells During Starvation.

PURPOSE: Müller cells support retinal neurons with essential functions. Here, we aim to examine the impact of starvation and oxidative stress on glutamate uptake and mitochondrial function in Müller cells. METHODS: Cultured human retinal Müller cells (MIO-M1) were exposed to H2O2 and additional starvation for 24 hours. Effects of starvation and H2O2 on glutamate uptake and mitochondrial function were assessed by kinetic glutamate uptake assays and Seahorse assays, respectively. Cell survival was evaluated by cell viability assays. mRNA and protein expressions were assessed by quantitative PCR and Western blot. RESULTS: Starvation of Müller cells increased the glutamate uptake capacity as well as the expression of the most abundant glutamate transporter, EAAT1. Mitochondrial and glycolytic activity were diminished in starved Müller cells despite unaffected cell viability. Simultaneous starvation and exposure to oxidative stress resulted in a reduced glutamate uptake and a collapsed mitochondrial function. In Müller cells with intact energy supply, the glutamate uptake and mitochondrial function were unaffected after exposure to oxidative stress. CONCLUSIONS: Here, we identify an increased susceptibility toward oxidative stress in starved Müller cells in spite of unaffected viability and an apparent decreased ability to transport glutamate. Solely exposure to oxidative stress did not affect Müller cell functions. Thus, our study suggests an increased susceptibility of Müller cells in case of more than one cellular stressor. Extrapolating these findings, age-related neurodegenerative retinal diseases may be the result of impaired Müller cell function.

Defective mitochondrial respiration, altered dNTP pools and reduced AP endonuclease 1 activity in peripheral blood mononuclear cells of Alzheimer's disease patients.

AIMS: Accurate biomarkers for early diagnosis of Alzheimer's disease (AD) are badly needed. Recent reports suggest that dysfunctional mitochondria and DNA damage are associated with AD development. In this report, we measured various cellular parameters, related to mitochondrial bioenergetics and DNA damage, in peripheral blood mononuclear cells (PBMCs) of AD and control participants, for biomarker discovery. METHODS: PBMCs were isolated from 53 patients with AD of mild to moderate degree and 30 age-matched healthy controls. Tests were performed on the PBMCs from as many of these participants as possible. We measured glycolysis and mitochondrial respiration fluxes using the Seahorse Bioscience flux analyzer, mitochondrial ROS production using flow cytometry, dNTP levels by way of a DNA polymerization assay, DNA strand breaks using the Fluorometric detection of Alkaline DNA Unwinding (FADU) assay, and APE1 incision activity (in cell lysates) on a DNA substrate containing an AP site (to estimate DNA repair efficiency). RESULTS: In the PBMCs of AD patients, we found reduced basal mitochondrial oxygen consumption, reduced proton leak, higher dATP level, and lower AP endonuclease 1 activity, depending on adjustments for gender and/or age. CONCLUSIONS: This study reveals impaired mitochondrial respiration, altered dNTP pools and reduced DNA repair activity in PBMCs of AD patients, thus suggesting that these biochemical activities may be useful as biomarkers for AD.

Functional examination of MLH1, MSH2, and MSH6 intronic mutations identified in Danish colorectal cancer patients.

BACKGROUND: Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomic rearrangements. However, a large number of mutations, including missense, silent, and intronic variants, are classified as variants of unknown clinical significance. METHODS: Intronic MLH1, MSH2, or MSH6 variants were investigated using in silico prediction tools and mini-gene assay to asses the effect on splicing. RESULTS: We describe in silico and in vitro characterization of nine intronic MLH1, MSH2, or MSH6 mutations identified in Danish colorectal cancer patients, of which four mutations are novel. The analysis revealed aberrant splicing of five mutations (MLH1 c.588 + 5G > A, MLH1 c.677 + 3A > T, MLH1 c.1732-2A > T, MSH2 c.1276 + 1G > T, and MSH2 c.1662-2A > C), while four mutations had no effect on splicing compared to wild type (MLH1 c.117-34A > T, MLH1 c.1039-8 T > A, MSH2 c.2459-18delT, and MSH6 c.3439-16C > T). CONCLUSIONS: In conclusion, we classify five MLH1/MSH2 mutations as pathogenic, whereas four MLH1/MSH2/MSH6 mutations are classified as neutral. This study supports the notion that in silico prediction tools and mini-gene assays are important for the classification of intronic variants, and thereby crucial for the genetic counseling of patients and their family members.

Natural selection of mitochondria during somatic lifetime promotes healthy aging.

Stimulation of mitochondrial biogenesis during life-time challenges both eliminates disadvantageous properties and drives adaptive selection of advantageous phenotypic variations. Intermittent fission and fusion of mitochondria provide specific targets for health promotion by brief temporal stressors, interspersed with periods of recovery and biogenesis. For mitochondria, the mechanisms of selection, variability, and heritability, are complicated by interaction of two independent genomes, including the multiple copies of DNA in each mitochondrion, as well as the shared nuclear genome of each cell. The mechanisms of stress-induced fission, followed by recovery-induced fusion and biogenesis, drive the improvement of mitochondrial functions, not only as directed by genotypic variations, but also as enabled by phenotypic diversity. Selective adaptation may explain unresolved aspects of aging, including the health effects of exercise, hypoxic and poisonous preconditioning, and tissue-specific mitochondrial differences. We propose that intermittent purposeful enhancement of mitochondrial biogenesis by stressful episodes with subsequent recovery paradoxically promotes adaptive mitochondrial health and continued healthy aging.