Research and resource needs for understanding host immune responses to SARS-CoV-2 and COVID-19 vaccines during aging.

On 16 and 17 March 2021, the National Institute of Allergy and Infectious Diseases and the National Institute of Aging convened a virtual workshop to discuss developments in SARS-CoV-2 research pertaining to immune responses in older adults, COVID-19 vaccines in both aged animals and older individuals, and to gain some perspective on the critical knowledge gaps that need addressing to establish scientific priorities for future research studies.

Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.

Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development.

Strategies to Prevent or Remediate Cancer and Treatment-Related Aging.

Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative.

Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors.

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or accentuated aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment.

Reverse geroscience: how does exposure to early diseases accelerate the age-related decline in health?

Aging is the major risk factor for both the development of chronic diseases and loss of functional capacity. Geroscience provides links among the biology of aging, the biology of disease, and the physiology of frailty, three fields where enormous progress has been made in the last few decades. While, previously, the focus was on the role of aging in susceptibility to disease and disability, the other side of this relationship, which is the contribution of disease to aging, has been less explored at the molecular/cellular level.

Workshop on immunizations in older adults: identifying future research agendas.

Goals for immunization in older adults may differ from those in young adults and children, in whom complete prevention of disease is the objective. Often, reduced hospitalization and death but also averting exacerbation of underlying chronic illness, functional decline, and frailty are important goals in the older age group. Because of the effect of age on dendritic cell function, T cell-mediated immune suppression, reduced proliferative capacity of T cells, and other immune responses, the efficacy of vaccines often wanes with advanced age.

Cloning and characterization of the presenilin-2 gene promoter.

Mutations in the presenilin-2 (PS-2) have been shown to cause early onset Alzheimer's disease (AD) in a series of families known as the Volga Germans and in an unrelated Italian kindred. Expression of the PS-2 gene is regulated during AD, aging, development and brain injury. Although expressed primarily in neurons, enhanced levels of PS-2 have been reported in astrocytes activated by neuronal damage.

Structure and alternative splicing of the presenilin-2 gene.

Missense mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes have been shown to be causes of autosomal dominant Alzheimer's disease (the AD3 and AD4 loci, respectively). Alternative splicing has previously been reported in the PS-1 gene. In this study, elucidation of intron/exon boundary sequences revealed that PS-2 is encoded by 10 coding exons.

The role of presenilin 1 in the genetics of Alzheimer's disease.

Approximately 75% of AD patients have an onset of the disease after the age of 60 years, and 60% of AD patients have no family history of the disease. Some cases of EOAD are clearly inherited in an autosomal-dominant manner. The beta APP gene on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 have all been characterized as genes in which mutations lead to familial EOAD.

Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence.

In an effort to identify new genes and analyse their expression patterns, 174,472 partial complementary DNA sequences (expressed sequence tags (ESTs)), totalling more than 52 million nucleotides of human DNA sequence, have been generated from 300 cDNA libraries constructed from 37 distinct organs and tissues. These ESTs have been combined with an additional 118,406 ESTs from the database dbEST, for a total of 83 million nucleotides, and treated as a shotgun sequence assembly project. The assembly process yielded 29,599 distinct tentative human consensus (THC) sequences and 58,384 non-overlapping ESTs.

Comparative expressed-sequence-tag analysis of differential gene expression profiles in PC-12 cells before and after nerve growth factor treatment.

Nerve growth factor-induced differentiation of adrenal chromaffin PC-12 cells to a neuronal phenotype involves alterations in gene expression and represents a model system to study neuronal differentiation. We have used the expressed-sequence-tag approach to identify approximately 600 differentially expressed mRNAs in untreated and nerve growth factor-treated PC-12 cells that encode proteins with diverse structural and biochemical functions. Many of these mRNAs encode proteins belonging to cellular pathways not previously known to be regulated by nerve growth factor.

Expression, cytoskeletal utilization and dimer formation of tropomyosin derived from retroviral-mediated cDNA transfer. Metabolism of tropomyosin from transduced cDNA.

Expression of the tropomyosin-1 isoform was enhanced by cDNA transfer in non-transformed murine 3T3 fibroblasts and also in v-Ki-ras transformed fibroblasts in which native tropomyosin-1 expression had been reduced and tropomyosin-2 synthesis virtually eliminated by action of the oncogene. The level of synthesis of insert-derived tropomyosin-1 was similar in normal and transformed transductants (3-5 times normal levels). The high level of insert-derived tropomyosin-1 expression resulted in a considerable increase in tropomyosin-1 utilization in the cytoskeleton of transformed cells, but this expression still did not reach normal levels, suggesting an oncogene-related inhibition of tropomyosin utilization.

Expression of transduced tropomyosin 1 cDNA suppresses neoplastic growth of cells transformed by the ras oncogene.

Synthesis of certain members of the tropomyosin family of microfilament-associated proteins is suppressed in fibroblasts neoplastically transformed by a number of retroviral oncogenes, by transforming growth factor alpha, and by chemical mutagens. To test whether tropomyosin suppression is a required event in neoplastic transformation, expression of one of two suppressed tropomyosins in NIH 3T3 mouse cells transformed by the ras oncogene was restored by retrovirally mediated cDNA transfer. Cells expressing the inserted cDNA showed partial restoration of microfilament bundle formation (which is typically deranged in transformed cells) together with increased cytoplasmic spreading.

T cell receptor activation induces rapid phosphorylation of prosolin, which mediates down-regulation of DNA synthesis in proliferating peripheral lymphocytes.

Prosolin is a major cytosolic phosphoprotein expressed prominently in rapidly proliferating human peripheral lymphocytes but produced at very low levels in resting (G0) PBL. It undergoes rapid phosphorylation upon treatment of growing cells with tumor-producing phorbol esters (TPA) and this phosphorylation event is correlated with a rapid down-regulation of DNA synthesis. In the present report we have studied various agents that, like TPA, act as partial or complete mitogens for G0 PBL and have determined their effect on phosphorylation of prosolin and on DNA synthesis in rapidly proliferating (IL-2-dependent) human PBL.

A specific defect of prosolin phosphorylation in T cell leukemic lymphoblasts is associated with impaired down-regulation of DNA synthesis.

Prosolin is a major cytosolic phosphoprotein of proliferating normal PBL. Treatment of growing PBL with phorbol ester (12-O-tetradecanoylphorbol-13-acetate (TPA)) or calcium ionophore (A23187) for 1 h caused phosphorylation of prosolin with the production of up to four prominent phosphorylated forms differing in degree of phosphorylation and/or two-dimensional electrophoretic mobility (peptides B to E). Formation of these phosphopeptides coincided with rapid down-regulation of DNA synthesis.

Accumulation and localization of troponin-T in developing hearts of Ambystoma mexicanum.

Troponin-T (Tn-T) expression in developing hearts of axolotls, Ambystoma mexicanum, was studied with the use of polyclonal and monoclonal antibodies and SDS-polyacrylamide gel electrophoresis. In precontractile hearts (stage 32/33), Tn-T was present in addition to myosin, actin and tropomyosin as evidenced by the presence of the protein bands in SDS-gels and by indirect immunofluorescence. Tn-T was localized in amorphous collections at the peripheries of these precontractile cells.

Immunofluorescence studies for myosin, alpha-actinin and tropomyosin in developing hearts of normal and cardiac lethal mutant Mexican axolotls, Ambystoma mexicanum.

Recessive mutant gene c in axolotl embryos results in an absence of normal heart function. Immunofluorescence studies were done to determine the distributions of myosin, tropomyosin and alpha-actinin in the hearts of normal and mutant siblings. Anti-myosin specifically stains the A bands of myofibrils in normal hearts and reveals a progressive increase in myofibril organization with development.