Diet and physical activity are thought to affect sustainable metabolic health and survival. To improve understanding, we studied survival of mice feeding a low-fat (LF) or high-saturated fat/high sugar (HFS) diet, each with or without free running wheel (RW) access. Additionally several endocrine and metabolic health indices were assessed at 6, 12, 18 and 24 months of age. As expected, HFS feeding left-shifted survival curve of mice compared to LF feeding, and this was associated with increased energy intake and increased (visceral/total) adiposity, liver triglycerides, and increased plasma cholesterol, corticosterone, HOMA-IR, and lowered adiponectin levels. Several of these health parameters improved (transiently) by RW access in HFS and LF fed mice (i.e., HOMA-IR, plasma corticosterone), others however deteriorated (transiently) by RW access only in HFS-fed mice (i.e., body adiposity, plasma resistin, and free cholesterol levels). Apart from these multiple and sometimes diverging health effects of RW access, RW access did not affect survival curves. Important to note, voluntary RW activity declined with age, but this effect was most pronounced in the HFS fed mice. These results thus challenge the hypothesis that voluntary wheel running can counteract HFS-induced deterioration of survival and metabolic health.