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In this paper, we aim to design an optimal sampler for a system in which fresh samples of a signal (source) are sent through an unreliable channel to a remote estimator, and acknowledgments are sent back over a feedback channel. Both the forward and feedback channels could have random transmission times due to time varying channel conditions. Motivated by distributed sensing, the estimator can estimate the real-time value of the source signal by combining the signal samples received through the channel and the noisy signal observations collected from a local sensor. We prove that the estimation error is a non-decreasing function of the Age of Information (AoI) for the received signal samples and design an optimal sampling strategy that minimizes the long-term average estimation error subject to a sampling rate constraint. The sampling strategy is also optimal for minimizing the long-term average of general non-decreasing functions of the AoI. The optimal sampler design follows a randomized threshold strategy: If the last transmission was successful, the source waits until the expected estimation error upon delivery exceeds a threshold and then sends out a new sample. If the last transmission fails, the source immediately sends out a new sample without waiting. The threshold is the root of a fixed-point equation and can be solved with low complexity (e.g., by bisection search). The optimal sampling strategy holds for general transmission time distributions of the forward and feedback channels. Numerical simulations are provided to compare different sampling policies.