Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states.

Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.

An aged immune system drives senescence and ageing of solid organs.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.

Inflammaging and the Skin.

As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation associated with aging, termed inflammaging. This is characterized by increased levels of circulating proinflammatory cytokines and a shift toward cellular senescence, changes that are believed to drive many age-associated conditions, including dementia, arthritis, and type 2 diabetes. As with other organs, the skin undergoes functional decline during aging, becoming more fragile and susceptible to infection; however, the contribution of inflammaging is not well-understood. This review article describes the evidence for inflammaging in the skin, its relationship with senescence, and how this relates to declining skin structure and function.

Diet restriction-induced healthy aging is mediated through the immune signaling component ZIP-2 in Caenorhabditis elegans.

Dietary restriction (DR) robustly delays the aging process in all animals tested so far. DR slows aging by negatively regulating the target of rapamycin (TOR) and S6 kinase (S6K) signaling pathway and thus inhibiting translation. Translation inhibition in C. elegans is known to activate the innate immune signal ZIP-2. Here, we show that ZIP-2 is activated in response to DR and in feeding-defective eat-2 mutants. Importantly, ZIP-2 contributes to the improvements in longevity and healthy aging, including mitochondrial integrity and physical ability, mediated by DR in C. elegans. We further show that ZIP-2 is activated upon inhibition of TOR/S6K signaling. However, DR-mediated activation of ZIP-2 does not require the TOR/S6K effector PHA-4/FOXA. Furthermore, zip-2 was not activated or required for longevity in daf-2 mutants, which mimic a low nutrition status. Thus, DR appears to activate ZIP-2 independently of PHA-4/FOXA and DAF-2. The link between DR, aging, and immune activation provides practical insight into the DR-induced benefits on health span and longevity.

The full spectrum of human naive T cells.

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.

HIV patients, healthy aging and transplant recipients can reveal the hidden footprints of CMV.

Cytomegalovirus (CMV) is a ß-herpesvirus. Latent infections are common in all populations. However age-associated increases in levels of CMV-reactive antibody are testament to repeated reactivations and periods of viral replication. CMV has been associated with several diseases of aging, including vasculopathy and neurocognitive impairment. These conditions occur at a younger age in persons with particularly high burdens of CMV - transplant recipients and people living with HIV. Here we define the "clinical footprints" as immunopathologies triggered by CMV that develop over many years. A high burden of CMV also drives accumulation of multifunctional terminally-differentiated αß T-cells, a novel population of Vδ2- γδ T-cells, and a population of CD56lo NK cells lacking a key regulatory molecule. An understanding of these "immunological footprints" of CMV may reveal how they collectively promote the "clinical footprints" of the virus. This is explored here in transplant recipients, HIV patients and healthy aging.

C-reactive protein and ageing.

Increasing evidence shows that C-reactive protein (CRP) is not only an inflammatory biomarker but also an important risk factor associated with ageing-related diseases including cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Recent studies have demonstrated that CRP is pathogenic in a number of diseases including hypertensive cardiovascular and kidney complications, diabetic nephropathy, and acute and chronic kidney diseases. It is well known that CRP binds its receptor, CD32/CD64, to induce the process of inflammation by activating the NF-κB signalling pathway. In addition, CRP mediates tissue fibrosis in a number of cardiovascular and kidney diseases by activating TGF-ß/Smad signalling via TGF-ß1-dependent and independent mechanisms. Furthermore, CRP is able to activate mTOR signalling in the diabetic conditions. Our recent studies also revealed that CRP impairs cell regeneration by causing the G1 cell cycle arrest and promotes ageing via a Smad3-dependent p21/p27 mechanism. In this review, we discuss the roles of CRP in ageing, with a focus on its function and mechanisms in physiological or "healthy" ageing, in ageing-related diseases, and in cell signalling.