Biology subjects

Covarrubias, A. J.

Publications and source records attributed to Covarrubias, A. J..

4 recordsLinked to original sources

bioRxiv2026

The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.

Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.

immunology↗

bioRxiv2026

Pathologic T cell immunosenescence drives the development of age-associated autoimmune peripheral neuropathy

While certain autoimmune conditions are more common in the young (e.g. Type 1 Diabetes), others are more frequent in the aged. A striking example is chronic inflammatory demyelinating polyneuropathy (CIDP), a CD4+ T cell-mediated autoimmune disease of the peripheral nervous system, which has a peak decade of onset of 70-79 years. How aging predisposes to autoimmunity, however, remains unclear. CD4+ T cells are highly susceptible to age-associated changes, including acquisition of immunosenescent features such as enhanced SA-{beta}-gal activity, increased Cdkn1a (p21) expression, and upregulation of Tnfsf8 (CD153). We show here that CD4+ T cells exhibiting these changes are increased in CIDP patients and mice with CIDP-like disease. These CD4+ T cells exhibit a senescence-associated secretory phenotype (SASP), show functional senescence (i.e., decreased proliferation and resistance to apoptosis), and have enhanced capacity for inciting neuropathy. Notably, a senescent cell-clearing senolytic agent (fisetin) decreased the pathogenic capacity of CD4+ T cells, and a SASP-suppressing senomorphic therapy (ruxolitinib) protected mice against autoimmune demyelination. Together, these findings delineate a key role for age-associated senescent CD4+ T cells in driving age-associated autoimmunity.

immunology↗

bioRxiv2023

Simultaneous Multi-Omics Analysis by Direct Infusion Mass Spectrometry (SMAD-MS)

Combined multi-omics analysis of proteomics, metabolomics, and lipidomics requires separate liquid chromatography-mass spectrometry (LC-MS), which limits throughput and increases costs, hindering the application of mass spectrometry-based multi-omics to large-scale analyses. Here, we present single-injection multi-omics analysis by direct infusion (SMAD), an integrated platform leveraging ion mobility mass spectrometry and self-developed software tools to enable single injection multi-omics analysis without liquid chromatography. SMAD allows quantification of over 9,000 metabolite m/z features and over 1,300 proteins from the same sample in less than five minutes. We validated the efficiency and reliability of SMAD with three case studies. (1) mouse macrophages after M1/M2 polarization and senescence, (2) a pilot drug screen in human cells, and (3) large-scale high-throughput drug screening of mammalian cells in 96-well plates. Finally, relationships between proteomic and metabolomic data are discovered by machine learning and validated.

systems biology↗

bioRxiv2019

Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38+ macrophages

Decline in tissue NAD levels during aging is linked to aging and its associated diseases. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues including visceral white adipose tissue and the liver during aging. Remarkably, these M1-like macrophages highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. We also find that senescent cells progressively accumulate in visceral white adipose tissue during aging and that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induce macrophages to proliferate and to express CD38. These results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and represent a novel therapeutic opportunity targeting maintenance of NAD levels during aging.

immunology↗