Aging is a complex process associated with progressive damage that leads to cellular dysfunction often accompanied by frailty and age-related diseases. Coping with all types of physiologic stress declines with age. While representing a primordial, cross-species response in poikilo- and homeotherms, the age-dependent perturbation of the stress response is more complex than previously thought. This short review examines how age influences the stress axis at multiple levels that involve both activating and attenuating pathways.

Emerging research demonstrates that social isolation and loneliness are linked to significant physical and mental health conditions. To address these concerns, the Tellegacy program was developed as an intergenerational health-promoting intervention to ameliorate older adult social isolation and loneliness in an effort to increase wellness. The purpose of this study was to reflect on testing of the Tellegacy program as a behavioral intervention. University students trained in goal setting, mindfulness, and listening strategies were paired with 11 older adults in the northern Midwest area via weekly in-person and phone conversations. Oral reminiscence therapies were used and books containing their stories were given to the older adults after participation. Older adults were surveyed using the University of California Los Angeles Loneliness Scale, Satisfaction of Life Scale, and patient health questionnaire-9 (PHQ-9) scale to elucidate the effectiveness of the intervention. Improved scores in loneliness, satisfaction of life, and PHQ-9 demonstrated favorable improvements in older adults. Additional benefits for the student Legacy Builder were revealed from self-reported changes. This suggests the potential benefits of structured encounters between trained students and isolated or lonely older adults. The Tellegacy intergenerational feasibility program warrants further studies to fully demonstrate its impact on health outcomes.

Brain aging is a major risk factor for cognitive diseases such as Alzheimer’s disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.

Colon cancer affects people of all ages. However, its frequency, as well as the related morbidity and mortality, are high among older adults. The complex physiological changes in the aging gut substantially limit the development of cancer therapies. Here, we identify a potentially unique intestinal microenvironment that is linked with an increased risk of colon cancer in older adults. Our findings show that aging markedly influenced persistent fucosylation of the apical surfaces of intestinal epithelial cells, which resulted in a favorable environment for tumor growth. Furthermore, our findings shed light on the importance of the host-commensal interaction, which facilitates the dysregulation of fucosylation and promotes tumor growth as people get older. We analyzed colonic microbial populations at the species level to find changes associated with aging that could contribute to the development of colon cancer. Analysis of single-cell RNA-sequencing data from previous publications identified distinct epithelial cell subtypes involved in dysregulated fucosylation in older adults. Overall, our study provides compelling evidence that excessive fucosylation is associated with the development of colon cancer, that age-related changes increase vulnerability to colon cancer, and that a dysbiosis in microbial diversity and metabolic changes in the homeostasis of older mice dysregulate fucosylation levels with age.

Age-dependent perturbation of the cellular stress response affects proteostasis and other key functions relevant to cellular action and survival. Central to age-related changes in the stress response is loss of heat shock factor 1 (HSF1)–DNA binding and transactivation properties. This report elucidates how age alters different checkpoints of HSF1 activation related to posttranslational modification and protein interactions. When comparing liver extracts from middle aged (12 M) and old (24 M) mice, significant differences are found in HSF1 phosphorylation and acetylation. HSF1 protein levels and messenger RNA decline with age, but its protein levels are stress-inducible and exempt from age-dependent changes. This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of HSF1 protein levels that are low in neurodegeneration and elevated in cancer.