Biology subjects

Rae, M.

Publications and source records attributed to Rae, M..

6 recordsLinked to original sources

bioRxiv2025

γδ T Cells Target and Ablate Senescent Cells in Aging and Alleviate Pulmonary Fibrosis

A variety of physiological and pathological stimuli elicit the cellular senescence response. Immune cells are known to execute surveillance of infected, cancerous, and senescent cells, and yet senescent cells accumulate with age and drive inflammation and age-related disease. Understanding the roles of different immune cells in senescent cell surveillance could enable the development of immunotherapies against biological aging and age-related disease. Here, we report the role of human gamma delta ({gamma}{delta}) T cells in eliminating senescent cells. Human donor V{gamma}9v{delta}2 T cells selectively remove senescent cells of different cell types and modes of induction while sparing healthy cells, with parallel findings in mouse cells. We find that senescent cells express high levels of multiple {gamma}{delta} T cell ligands, including cell-surface BTN3A1. Individually blocking NKG2D or {gamma}{delta} TCR of {gamma}{delta} T cells only partially reduces V{gamma}9v{delta}2 T cell cytotoxicity, evidencing their versatility in senescence removal. {gamma}{delta} T cells expand in response to the induction of a mouse model of idiopathic pulmonary fibrosis (IPF), accompanied by the emergence of senescent cells, and colocalize with senescent cells in lung tissue from patients with IPF. Finally, we show that adoptive cell transfer of {gamma}{delta} T cells into an IPF mouse model reduces the number of p21-expressing senescent cells in affected lung tissue and improves outcomes. {gamma}{delta} T cells or modalities that activate their surveillance activity present a potent approach for removing senescent cells and their attendant contribution to aging and disease.

immunology↗

bioRxiv2025

Inhibition of PIKfyve kinase induces senescent cell death by suppressing lysosomal exocytosis and leads to improved outcomes in a mouse model of idiopathic pulmonary fibrosis

Cellular senescence is a pivotal hallmark of aging, which limits lifespan and contributes to the development of age-related diseases. Efforts to identify senolytics - drugs that selectively eliminate senescent cells, have so far yielded candidates with limited translational potential. Here, we characterize the senescent cell surface proteomic landscape and identify proteins that are abnormally present on the plasma membrane of senescent cells. Many of these proteins are lysosomal enzymes, pointing to lysosomal exocytosis as a likely mechanism that leads to their persistent display on the cell surface. Blocking lysosomal exocytosis via PIKfyve kinase inhibition with a small molecule drug apilimod results in selective killing of senescent cells in vitro, while this treatment does not affect quiescent and proliferating cells. Furthermore, apilimod can be safely administered in vivo and effectively removes senescent cells and reduces tissue remodeling in a bleomycin mouse model of pulmonary fibrosis. We conclude that apilimod is an effective and well-tolerated senolytic that may be useful for the treatment of senescence-associated diseases of aging.

molecular biology↗

bioRxiv2025

Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis

The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1+ cells express high levels of prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1- cells. The percentage of Lamp1+ cells is increased in mice with fibrotic lungs after bleomycin instillation. Finally, we use a dual antibody-drug conjugate (ADC) strategy to eliminate LAMP1+ senescent cells.

molecular biology↗

bioRxiv2025

Analysis of the current state of frailty indexes and their implementation for aging intervention studies

Animal lifespan studies are foundational to developing interventions against the biological aging process. In recent years, there has been rising interest in characterizing the effects of longevity therapeutics on health span. Frailty indexes, originally developed to assess clinical frailty in aging humans, have shown promise as measurements of biological age and have been adopted for use in rodent aging biology. This perspective looks at the current state of rodent frailty indexes and how they are implemented. The differences in frailty parameters used to calculate these indexes have led to inconsistencies between studies defining frailty. In this perspective, we have highlighted those differences and made recommendations for implementing protocols for frailty index measurement.

animal behavior and cognition↗

bioRxiv2022

Evolutionary survival strategies of the female giant panda: optimizing energy resources and expenditure prior to pregnancy by postponing corpus luteum reactivation

The giant panda reproductive physiology shows important similarities with at least six of the eight existing bear species: the occurrence of diapause and/or pseudopregnancy is commonly described in bears. Nevertheless, significant differences including the earlier breeding season with - in general - a single estrus, a shorter delay of implantation and a more variable birth season, indicate an evolutionary adaptation from the seasonal reproductive traits described in hibernating bear species. In this study we aimed to determine true pregnancy length for giant pandas and to open the discussion on the peculiarities of giant panda reproductive biology, more specifically focusing on the rationale behind their short-seasoned reproductive cycle compared to the other bear species. For this purpose, metabolic (body weight and fecal output) profiles were matched with endocrine changes, mainly urinary progesterone metabolites, in 5 pregnant, 8 non-birth and 6 pseudopregnant cycles of 6 female giant pandas. Pregnancy in giant pandas lasts only 42 days from early reactivation of the corpora lutea (CLs) until birth. In addition, our findings urged the need to redefine the generally accepted biphasic progesterone profile into a triphasic primary progesterone rise (corpus luteum dormancy (CLD) I, II and III) prior to entering the active luteal phase (= secondary progesterone rise). Two episodes of progesterone increase (CLDII: 81.20 {+/-} 5.85 days versus CLDIII: 60.80 {+/-} 3.83 days prior to birth for pregnant cycles) were identified, respectively corresponding to CL reactivation (74-88 days prior to birth) and implantation ({+/-} 60 days prior to birth) in other bear species. The progesterone concentration during CLDIII was higher in pregnant cycles, indicating a potential communication between maternal tissues and blastocyst(s) enhancing progesterone concentrations and thus allowing optimal priming of uterine tissues to better prepare for blastocyst reactivation/development. Compared with other bear species, giant pandas seem to shorten the active luteal phase, and thus pregnancy, by approximately 30 days by actively postponing CL reactivation. Potential mechanisms in play overruling and suppressing the evolutionary conserved photoperiodical triggers of CL reactivation are discussed while a parallel study will further elaborate on the CL dynamics during giant panda gestation.

evolutionary biology↗

bioRxiv2022

Endogenous IL-10 Contributes to Wound Healing and Regulates Tissue Repair

BackgroundInterleukin-10 (IL-10) is essential in fetal regenerative wound healing and likewise promotes a regenerative phenotype in adult dermal wounds. However, the role of endogenous IL-10 in postnatal dermal wound healing is not well established. We sought to determine the role of IL-10 in murine full thickness, excisional wounds that are splinted to prevent contracture and mimic human patterns of wound closure. MethodsFull thickness, excisional wounds were made in wildtype (WT) and IL-10-/- mice on a C57BL/6J background (F/M, 8wks old). In a subset of wounds, contraction was prevented by splinting with silicone stents (stenting) and maintaining a moist wound microenvironment using a semi-occlusive dressing. Wounds were examined for re-epithelialization, granulation tissue deposition, and inflammatory cell infiltrate at day 7 and fibrosis and scarring at day 30 post-wounding. ResultsWe observed no difference in wound healing rate between WT and IL-10-/- mice in either the stented or unstented group. At day 7, unstented IL-10-/- wounds had a larger granulation tissue area and more inflammatory infiltrate than their WT counterparts. However, we did observe more F4/80+ cell infiltrate in stented IL-10-/- wounds at day 7. At day 30, stented wounds had increased scar area and epithelial thickness compared to unstented wounds. ConclusionsThese data suggest that endogenous IL-10 expression does not alter closure of full thickness excisional wounds when wound hydration and excessive contraction are controlled. However, the loss of IL-10 leads to increased inflammatory cell infiltration and scarring. These data suggest that previous reports of increased rates of healing in IL-10-/- mice ought to be revisited considering recent advances in wound healing models. Moreover, these new findings suggest that IL-10 contributes to regulation of inflammation without compromising the healing response.

molecular biology↗