Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04842864 |
| Other study ID # |
2021-12857 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 19, 2021 |
| Est. completion date |
February 1, 2023 |
Study information
| Verified date |
August 2022 |
| Source |
Montefiore Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Autophagy, which involves the degradation of aged or damaged cellular components, has been
shown to extend healthspan and lifespan in multiple organisms, including flies, worms, and
mice. Research has also demonstrated that autophagy declines with age in these simpler
experimental models. However, human studies are lacking. Our study seeks to determine whether
fasting, a robust stimulus of autophagy, upregulates autophagy in humans, and whether
autophagy is reduced in healthy older people compared to healthy younger individuals.
Description:
Autophagy is a cellular quality control pathway that degrades aged or damaged organelles and
protein aggregates within lysosomes. By doing so, autophagy provides an alternate source of
energy for cells to cope with adverse conditions. The level of autophagy determines the
degree to which aged cells are able to eliminate damaged organelles and/or toxic aggregates
and mount a protective response against stress. At the physiological level, nutrient
deprivation or fasting is one of the most robust stimuli for autophagy across diverse
experimental systems.1 Our lab has shown important roles for autophagy in lipid/glucose
homeostasis and regulation of energy balance. We have found that autophagy degrades cellular
lipid stores via a process we described as lipophagy. We have also shown contributions of
autophagy to the regulation of feeding as well as its developmental roles in maintenance of
muscle and fat mass. In addition to these physiological functions, a number of studies have
revealed that mice lacking autophagy in the central nervous system show rapid onset of
neurodegeneration and an early death.2,3 These studies support a central role of autophagy in
the maintenance of healthspan.
It is well-established that autophagy activity declines with age, which has led to the
hypothesis that autophagy failure contributes to the metabolic syndrome of aging. In fact,
young mice with tissue-specific knockout of the autophagy gene Atg7 display features of
aging, including loss of muscle mass (mimicking sarcopenia of aging), fatty liver, decreased
adipose lipolysis, de-differentiation of brown fat, and pancreatic β-cell dysfunction.4-6
Conversely, restoration of autophagy via pharmacological or genetic approaches prevents
age-associated decline in cell function and improves stress response-thus directly extending
healthspan. As a consequence, there is great interest in developing new experimental
approaches to prevent age-associated chronic diseases. In fact, caloric restriction (CR) has
been shown to stimulate autophagy and extend lifespan and healthspan in multiple experimental
models. While these CR studies were carried out in simpler organisms, such as flies, worms,
and mice,7-9 similar studies in humans are largely lacking. Since autophagy is activated by
starvation, the prevailing hypothesis is that caloric restriction (CR) or more physiological
approaches such as intermittent fasting will stimulate autophagy in humans, which in turn
will prevent or retard the onset of age-associated chronic diseases. There is limited
knowledge if indeed extended periods of fasting will activate autophagy in humans. In
addition, we do not know what duration of fasting may be required to stimulate autophagy in
humans. Finally, we do not know if, nor by how much, fasting-induced autophagy is reduced in
aging humans. Due to the aforementioned gaps in our knowledge regarding autophagy in humans,
in this study we will test the ability of extended periods of restriction to food to
stimulate autophagy in healthy, young individuals. Further, we will compare the extent to
which autophagy is reduced in healthy older subjects, when compared to those observed in
young controls. In our study, we will be using samples of adipose tissue, a metabolically
active endocrine organ, and peripheral blood cells, which have both been evaluated in prior
autophagy studies and can be obtained in a less invasive manner.
