CHARTING THE TOKEN OF TIME: YAP/TAZ TRANSCRIPTIONAL REGULATORS AT THE ROOTS OF AGING

Introduction

A major challenge in aging research is to distinguish which age-related alterations play a driving role and their interconnections. Aging ultimately implies dysregulated transcription; yet, the identity of signaling cascades and transcription factors that control youthfulness and aging in adult tissues remains poorly understood.

Communication Changes

Aging also entails maladaptive changes in how cells communicate with each other and their surrounding extracellular matrix (ECM). Senolytic approaches have revealed the role of senescent cells as drivers of aging, leaving, however, unclear what cell types first become senescent in real tissue and why.

Research Aim

Here, we aim to address and connect these fundamental unknowns into an integrative view of aging at an unprecedented spatial, temporal, molecular, and mechanistic resolution.

Preliminary Results

As preliminary results, we report that aging requires decreased activity of YAP/TAZ mechanosensors in stromal cells leading to unscheduled activation of cGAS/STING signaling. Aging may be halted by restoring a youthful YAP/TAZ-cGAS/STING signaling balance.

Hypothesis

But why do we age then? Building on these findings, our hypothesis is that aging initiates from deterioration of our own “structural frames”:

1. Changes in spatial/contextual signals that cells perceive from the ECM
2. Altered mechanotransduction
3. Increased fragility of the nuclear envelope leading to cell senescence

These processes are reversible, and understanding them may reveal new routes to halt aging.

Methodology

For this, we will chart and functionally interrogate a multidimensional atlas of aging biology, delving into the logics of tissue physiology and its progressive degeneration over a lifetime, also implementing novel methodologies.

Unique Vantage Point

Our YAP/TAZ prism offers a unique vantage point to dissect causally relevant extracellular and intracellular mechanisms of youthfulness vs. aging. This opens the exploration of aging remedies to restore youthful tissue ecosystems by restoring youthful YAP/TAZ activity.