# Complement Components as Mediators of Cell and Tissue Aging

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2020 · $443,558

## Abstract

PROJECT SUMMARY/ABSTRACT
 Age-related changes in cellular functions are influenced by the local and systemic environment in which a
cell resides. This has been demonstrated unequivocally by heterochronic studies in which aged cells are
introduced or exposed to a more youthful environment, resulting in enhanced cellular function reminiscent of
more youthful counterparts. Conversely, young cells exposed to an aged environment adopt a more aged
phenotype. These findings all point to circulating factors that may profoundly influence cellular aging. In the
studies of this proposal, we seek to extend our own findings that emerged from studies of heterochronic
parabiotic mice implicating active Wnt signaling, mediated by one or more systemic factors, as a driver of
muscle stem cell (MuSC) aging. It was later shown that a component of the complement cascade, C1q,
increased in the blood with age, is capable of activating Wnt signaling in cells, and is responsible for age-
related impairment in muscle regeneration, although the cellular targets were not identified. C1q has
subsequently been shown to function independent of the classic cascade in multiple physiologic processes and
to drive aging in a variety of tissues. For the studies of this proposal, we will seek to explore the mechanisms
by which C1q inhibits muscle regeneration by exploring the cellular targets and signaling cascades associated
with C1q activity. Toward these goals, the Specific Aims of this proposal are (1) to study the mechanism by
which C1q promotes the age-related decline in muscle regenerative potential (and specifically whether MuSCs
are the direct target); (2) to test whether C1q promotes cellular aging by inducing TGFβ signaling (based on
evidence we and others have obtained in previous studies of this pathway being downstream of Wnt signaling
and a mediator of MuSC aging); and (3) to test whether C1q promotes age-related fibrogenesis in skeletal
muscle by acting directly on fibroadipogenic progenitors (FAPs) (to examine the cellular mechanism of the
demonstrated effects of C1q in promoting muscle fibrosis). Together, these studies will expand our
understanding of the effects and mechanisms of this systemic mediator of cellular aging and the exciting new
findings of non-canonical mechanisms of complement components and their newly discovered roles in tissue
aging.

## Key facts

- **NIH application ID:** 9921279
- **Project number:** 5R01AG055755-04
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** THOMAS A. RANDO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,558
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921279

## Citation

> US National Institutes of Health, RePORTER application 9921279, Complement Components as Mediators of Cell and Tissue Aging (5R01AG055755-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9921279. Licensed CC0.

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