However, there are several reasons

However, there are several reasons to question whether or not rapamycin administered late in life will actually improve physical function and hence healthspan given that (a) in almost every case, rapamycin reduces body weight making dissociation of the direct action of rapamycin from the effects of changes in body weight and/or food consumption muddled; (b) rapamycin blocks mTOR, a protein that is already reduced in aged muscle and is essential for cell maintenance and nutrientsensing, calling into question the impact of further reducing signaling in this system; and (c) rapamycin has been shown to impair glucose functioning, which in older organisms is universally disrupted, directly associated with declining physical performance, and could potentially become exacerbated with rapamycin treatment (8). We attempt to address in this article and in our companion article (18), these reservations by examining rapamycin’s role in the alteration of several physiological and behavioral outcomes, indicative of healthspan, in a rodent model of aging and to directly compare rapamycin treatment with an IF protocol to determine commonalities and differences between these two life-spanenhancing interventions on healthspan. Table 1 provides a summary of the effects of 5 weeks of rapamycin or IF treatment and the specifics are discussed below.First, rapamycin in almost every case induces weight loss in old and young animals. In the clinical literature, controversy exists regarding the circumstances under which older adults should be advised to lose weight and in some cases, weight loss is associated with increased mortality and acceleration of declining function (19–22). This most likely is associated within which body compartment (eg, muscle vs adipose tissue) the weight loss occurs. Thus, elucidating how rapamycin affects weight loss is critical. As stated previously, it is also critical to dissociate the body weight and/or food consumption effects of rapamycin from the direct pharmacological action of the compound itself.To address both of these questions, we opted to compare rapamycin treatment with a group of young and old rats undergoing an IF protocol. Our IF protocol mimics the rapamycin treatment protocol in so far as animals are receiving “treatment” approximately every other day, and more importantly, results in a food consumption and body weight pattern that is similar to that following rapamycin treatment. Furthermore, rats exposed to such an IF regimen when given the opportunity on feeding days do not completely compensate for their lack of food on nonfeeding days thereby resulting in approximately a 25%–30% reduction in food intake (this study) (23). This is in contrast to some strains of mice that actually make up for the majority of the lost opportunity to eat and only demonstrate a 10% reduction in body weight (24). Interestingly, although dependent on strain and age of initiation,both rats and mice experience increased maximal life span (23,24)