News & Views in 2022

There are no current standard-of-care treatments for sarcopenia, an age-associated decline in muscle mass and strength. A new study shows that genetically or pharmacologically countering the age-associated accumulation of sphingolipids in skeletal muscle can ameliorate sarcopenia in mice. The authors also identify genetic variants linked to sphingolipid biosynthesis that associate with muscle function in aged humans.

In our aging global population and with no effective treatments, the cognitive impairments associated with Alzheimer’s disease represent a major healthcare problem. A recent study in Nature Aging highlights intermittent fasting as a potential way to decrease the progression of Alzheimer’s disease in mice through changes to the gut microbiota.

Aging is associated with an accumulation of myeloid-biased hematopoietic stem cells with reduced regenerative potential, but the underlying mechanisms remain unclear. A study by Wendorff et al. demonstrates that inactivation of a single epigenetic regulator — the plant homeodomain factor 6 (PHF6) — transcriptionally and functionally rejuvenates mouse aged hematopoietic stem cells.

A new study shows that decreased cystatin A synthesis in aged epidermis mediates age-related bone loss, whereas topical treatment that restores cystatin A mitigates this loss. This report demonstrates that skin aging has systemic consequences by showing that signals originating in skin can control bone function.

Elder abuse has been recognized as a serious problem for decades. Yet rigorous studies are rare. Burnes and colleagues move the field forward by identifying how pervasive the problem is, the factors that increase and decease vulnerability, and how these factors change over a three-year period.

While C. elegans males are known to induce demise of hermaphrodites, the mechanism underlying this phenomenon is poorly understood. Through transcriptomic analyses, Booth et al. identify specific hermaphrodite gene sets that respond to male pheromones, sperm and seminal fluid and can mediate premature death of hermaphrodites.

Mouse frailty can be measured with a frailty index by manually counting health deficits. Vivek Kumar and colleagues use machine learning to extract physical performance deficits from video data to create a ‘visual frailty index’. This automated technique may facilitate high-throughput research into new frailty interventions.

Lee and colleagues reveal a previously unrecognized population of astrocytes in the aged brain with disrupted proteostatic signaling that generates defects in astrocyte morphology, protein trafficking and synapse maintenance in the aging hippocampus.

Genetic variation linked to lower levels of soluble ST2, a decoy cytokine receptor for IL-33, may protect against Alzheimer’s disease in women carrying the APOEε4 allele by increasing microglial plaque removal. This discovery advances our understanding of the immune system’s role in Alzheimer’s disease and underscores the importance of sex-specific disease processes.

The microenvironment can regulate adult stem cell function during tissue homeostasis and regeneration, but whether and how this is altered in aging is unclear. Ichijo et al. find that increased dermal stiffness, as a result of vasculature atrophy, activates cation channel PIEZO1, leading to interfollicular epidermal stem cell dysregulation.

Muscle function decreases with age, and there are few preventative treatments. Zhang et al. find that different cell types in aging muscle express different senescence markers, giving insight into the complexity of senescence biology. They also show that aspects of muscle aging can be improved with senotherapeutic intervention.

Transcription factors can control cell identity and function in health and disease. However, how they do so during aging is incompletely explored. Maity and colleagues identify age-related changes in gene regulation by analyzing the expression patterns of transcription-factor target genes in single-cell transcriptomics data.

Compromised clearance of dysfunctional mitochondria, through the process of mitophagy, has garnered attention as an essential contributor to aging and neurodegeneration. Schmid and colleagues¹ reveal that genetic enhancement of mitophagy via neuronal overexpression of BNIP3 alleviates brain aging and prolongs healthspan in fruit flies.

Tau neuropathology is a defining feature of Alzheimer’s disease. For decades, its progression throughout the cortex has been captured post mortem using Braak stages. A new study replicated Braak staging in living patients using positron emission tomography, showing associations with other biomarkers and clinical deficits.

Aging is accompanied by a gradual decline of cell proliferation potential. FOXM1 is a transcription factor involved in cellular proliferation and cell cycle progression. Ribeiro et al. show that cyclic expression of a truncated form of a FOXM1 transgene in vivo can delay senescence-associated progeroid and natural aging phenotypes in mice.

Public health policies recommend maintaining a body mass index below 25, after which individuals are considered to be overweight or obese. A new study looked at optimal BMI in adults in China in their ninth decade or older, and concludes that these recommendations need to be revised upwards in this age group.

Neurodegenerative diseases, including Parkinson’s disease, are linked to the accumulation of defective mitochondria in the brain and to microbial dysbiosis in the gut. However, the interplay between these factors is incompletely understood. Fedele et al. reveal how gut mitochondrial dysfunction activates intestinal inflammation to drive neurodegeneration in a Parkinson’s disease model.

Frailty is an important age-related prognostic for mortality, and little is known about its immune landscape. Luo et al.¹ use single-cell profiling to gather a comprehensive understanding of immune changes that happen from birth to old age, and provide new insights into the often-overlooked state of frailty.

Apolipoprotein E (APOE) is an important regulator of lipid metabolism and is genetically associated with longevity and age-related diseases such as Alzheimer’s disease. However, the molecular mechanisms that link APOE and aging are incompletely understood. Now an article in Nature Aging reveals that nuclear APOE promotes senescence by destabilizing heterochromatin.

While investigating sex differences in T cell aging, Mkhikian et al. identified a role for excessive IL-7 signaling and N-glycan branching in age-related T cell dysfunction in women and female mice. These findings point to the increasingly recognized importance of the effects of biological sex on immune aging, and delineate new targetable pathways in age-related immune dysfunction.