Donald A. Jurivich

Relation of High Heart Rate Variability to Healthy Longevity

The populations aging underscores the need to understand the process and define the physiologic markers predictive of healthy longevity. The findings that aging is associated with a progressive decrease in heart rate variability (HRV), an index of autonomic function, suggests that longevity might depend on preservation of autonomic function. However, little is known about late life changes. We assessed the relation between autonomic function and longevity by a cross-sectional study of HRV of 344 healthy subjects, 10 to 99 years old. The HRV was determined from 24-hour Holter records, using 4 time domain measures of HRV (the root mean square of the successive normal sinus RR interval difference [rMSSD], percentage of successive normal sinus RR intervals >50 ms [pNN50], standard deviation of all normal sinus RR intervals during a 24-hour period [SDNN], and standard deviation of the averaged normal sinus RR intervals for all 5-minute segments [SDANN]). Autonomic modulation of the 4 measures differs, permitting distinctions between changes in HRV-parasympathetic function, using rMSSD and pNN50, and HRV-sympathetic function using SDNN and SDANN. Decade values were compared using analysis of variance and t-multiple comparison testing. The HRV of all measures decreases rapidly from the second to fifth decades. It then slows. The HRV-sympathetic function continues to decrease throughout life. In contrast, the decrease in HRV-parasympathetic function reaches its nadir in the eighth decade, followed by reversal and a progressive increase to higher levels (p <0.05), more characteristic of a younger population. In conclusion, healthy longevity depends on preservation of autonomic function, in particular, HRV-parasympathetic function, despite the early age-related decrease. The eighth decade reversal of the decrease in HRV-parasympathetic function and its subsequent increase are key determinants of longevity. Persistently high HRV in the elderly represents a marker predictive of longevity.

Clonal senescence alters endothelial ICAM-1 function

Little is known how age alters the dynamics and function of cell adhesion molecules, especially under inflammatory and stressful conditions. One membrane constituent, intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein of the immunoglobulin (Ig) superfamily that regulates key outside-->in and inside-->out signals associated with cell-to-cell interactions. If conditions such as age and inflammation change usual ICAM-1 action then important downstream effects ultimately perturb endothelial cell function. In this report, ICAM-1 accumulates in late passage endothelial cells when compared to early passage endothelial cells, yet ICAM-1 protein expression is attenuated when senescent cells are challenged by TNF-alpha (10ng/ml). Importantly, age alters ICAM-1 dynamic properties from directed to random receptor motion within the membrane. Single particle tracking reveals that the average ICAM-1 mobility is 44% less in late than early passage cells after its motion is stimulated by the Protein Kinase C (PKC) activator, phorbol myristate acetate (PMA). The mechanism for altered ICAM-1 mobility partly can be explained by a reduced rate of alpha-actinin linking with ICAM-1 in late passage Human Pulmonary Artery Endothelial Cells (HPAECs). Furthermore, tyrosine phosphorylation of alpha-actinin, a requirment for ICAM-1 clustering, is markedly reduced in senescent cells. These findings support a hypothesis that senescence results in changes of ICAM-1 activation and clustering, thus resulting in an age-dependent transmembrane signaling disorder. Therefore, further understanding of age-dependent disturbances of ICAM-1 regulation during inflammation can provide important clues as to appropriate targets for therapeutic interventions and prevention of vascular disorders in elderly at the level of the endothelial surface membrane.

Human aging alters the first phase of the molecular response to stress in T-cells

This study examines how age affects the first phase of the heat shock response in human T-cells. To understand how age alters transcriptional regulation of the heat shock genes, a cross-sectional study was conducted utilizing human T-cells enriched from peripheral blood lymphocytes of healthy young (20-40 years old) and old (>70 years old) donors. Nuclear run-on analysis revealed a 66% reduction in hsp70 transcription rates in old compared to young nuclei harvested from T-cells exposed to a brief 42 degrees C heat shock. To determine if one or more protein transactivators of the proximal and distal promoter regions of the hsp70 gene were affected by age, gel shift analysis was performed. Both HSF1 and SP1 DNA-binding were reduced with age but no reduction was noted in CCAAT-DNA binding. Western blot analysis indicated that HSF1 but not HSF2 protein levels were reduced in aged donor samples. These data suggest that human T-cell senescence involves a multi-factorial mechanism that diminishes an important transcriptional response to thermal stress. The results are discussed relative to recent studies that support a multi-factorial mechanism for age-dependent attenuation of the heat shock transcription factor.

Co-Learning With Home Care Aides and Their Clients: Collaboratively Increasing Individual and Organizational Capacities

Changes in health care provide unprecedented opportunities for collaboration across research, education, and practice for the common goal of enhancing the well-being of older adults and their caregivers. This article describes how a pilot project, Promoting Seniors’ Health with Home Care Aides, has synergistic education, research, and practice effects that enhance individual and organizational capacities. This pilot is an innovative partnership with home care aides to deliver a safe physical activity program appropriate for frail seniors in a real-life public home care program. The intervention and research occur in older adults’ homes and thus provide rare opportunities for the research team and partners to learn from each other about dynamics of home care in older adults’ life contexts. Co-learning is essential for continuous quality improvement in education, research and practice. The authors propose to establish “teaching home care” to ensure ongoing co-learning in gerontology and geriatrics.

Multiple Myeloma in the Very Old: An IASIA Conference Report

Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population.

Acteylcholinesterase inhibitor rivastigmine enhances cellular defenses in neuronal and macrophage-like cell lines

Neuroprotection mediated by the cellular heat shock response offers 1 clinical strategy to prevent, stabilize, and possibly reverse neurodegenerative processes. Although damaged proteins are thought to be the primary stimulus for the heat shock response, several studies indicate that pharmaceutical agents can either directly induce the heat shock transcription factor (Hsf1) or enhance its activation during different forms of cellular stress. Because Hsf1 is now known to combat the proteotoxicity of aging and has a central role in modulating amyloid aggregation, pharmacologic interventions to strengthen Hsf1 action may have important implications for preventing neurodegeneration linked to altered and damaged proteins such as observed in Alzheimers disease. Given reports that some agents for the treatment of Alzheimers disease have neuroprotective properties, this project investigated whether rivastigmine, which is an acetyl and butaryl cholinesterase inhibitor, mediates the neuroprotection of the neuronal-like cell line SH-SY5Y. The cells were exposed to various concentrations of rivastigmine to determine whether the drug protected cells from toxic injury and induced the 1st phase of the cellular heat shock response. In all, 100-micromol/L rivastigmine decreases cell death by 40% compared with untreated cells. This concentration enhances Hsf1 activation by strengthening both its multimerization and its phosphorylation, which leads to increased messenger RNA (mRNA) for hsp70. Therefore, one of the putative neuroprotective mechanisms of rivastigmine seems to be mediated through the heat shock response. These results also are observed in cultured macrophage-like cells, which suggests a future clinical tool for monitoring pharmacologically improved stress responses in peripheral blood mononuclear cells during treatment of Alzheimer disease.

Ultraviolet light attenuates heat-inducible gene expression

Ultraviolet light (UV) induces a stress response mediated through transcription factors such as NF‐kB and AP‐1, yet little is known about its effect on other transactivators of stress gene expression such as heat shock factor (HSF1). Analysis of UV‐treated HeLa cells unexpectedly revealed uncoupling of the heat shock response. UV weakly induced HSF1 into its DNA bound state and markedly attenuated heat‐inducible gene expression. HSF1 was further analyzed as a potential target for the uncharacteristic uncoupling of the thermal stress response by another type of stress. Heat‐inducible multimerization and nuclear translocation of HSF1 were found to be intact in UV‐treated cells; however, the monomeric rather than the multimeric form of HSF1 become hyperphosphorylated by UV. This effect could be partially abolished by the antioxidant N‐acetyl cysteine with partial reconstitution of hs gene expression. The reported role of a MAP kinase blockade of HSF1 transactivating properties could not be confirmed by an inhibitor of the MAP kinase pathway. Fibroblasts defective in SAP kinase activity also did not exhibit resistance to UV‐inducible phosphorylation of HSF1. Two‐dimensional phosphopeptide mapping of HSF1 revealed a single tryptic peptide to be affected by UV, but no new pattern of phosphorylation was evident relative to tryptic phosphopeptide profile observed in control cells. These data suggest that UV uncoupling of the hs response possibly involves steps in addition to those associated with phosphorylation the monomeric form of HSF1. J. Cell. Physiol. 172:314–322, 1997.

Engineered Repeated Electromagnetic Field Shock Therapy for Cellular Senescence and Age-Related Diseases

A new consensus of gerontologists proposes that delay of biological senescence is the most potent public health measure for preventing chronic disease in late life. At the most fundamental level, cellular aging is characterized by a decline in repair and homeostatic systems. Thus, interventions that protect or rejuvenate these cellular systems hold significant promise for preventing or delaying the onset of age-related diseases. The most likely candidates for delaying senescence are the longevity-linked transcription factors DAF16 and HSF1. If one were to engineer negligible senescence, a key target would be the heat shock protein axis regulated by HSF1. This pathway is the preferred pathway to prevent protein damage or aggregation, whereas DAF-16/FOXO is a backup pathway activated during stress. Reduced HSF1 activity appears to accelerate tissue aging and shortens life span. Conversely, over-expression of HSF1 increases life span and decreases amyloid toxicity in animal models. This paper describes enhancement of the HSR/HSF1 pathway engineered by repeated electromagnetic field shock (REMFS). In a recent study, we demonstrated that REMFS therapy upregulates the HSR/HSF1 pathway, delays cellular senescence in young cells, and transiently reverses it in senescent cells, thus altering cellular mortality. The technology of applying certain beneficial EMF energy to the human body to stimulate the natural stress response and activate the repair and maintenance systems is a new strategy for engineered negligible senescence. We discuss the exciting clinical implications of REMFS therapy in human aging and disease.

Integrating Geriatrics Knowledge into a Medical Student Clerkship Using Twitter Poll: GERIATRIC TWITTER POLL FOR MEDICAL EDUCATION

A controlled, prospective, 2‐year cohort observational study was conducted to test whether weekly geriatric questions delivered through Twitter Poll could improve geriatrics knowledge during an internal medicine clerkship for third‐year medical students. Pre‐ and post‐rotation test results used a modified University of California, Los Angeles geriatric knowledge test that included questions linked to 26 Association of American Medical Colleges geriatric competencies for medical students. Data were analyzed using a general linear model repeated‐measure design and Student t‐test. The primary outcome showed that Twitter Poll participants had more than twice the geriatrics knowledge (p = .002) than students who did not use Twitter Poll. Subset analysis showed different test performances according to sex (p = .03), training site (p = .002), and cohort (p = .003). This study is the first demonstration of Twitter Poll efficacy in medical education and raises questions about whether it could be even more effective if linked to spaced timing of didactic content or supported by annotated answers to geriatrics questions. J Am Geriatr Soc 66:2389–2393, 2018.