Interfering in an Amplification Loop for Oxidative Stress in Aging Mice
Researchers here report on the identification of a mechanism in mice that amplifies the harms done by an excess of oxidative molecules. Aging is accompanied by a general increase in oxidative stress in cells, and suppressing this amplication mechanism is shown to improve measures of health and slow the progression of aspects of aging. This is similar in spirit to a number of other lines of research that seek to attenuate oxidative stress in old tissue, such as the use of mitochondrially targeted antioxidants, but tackling the challenge at a completely different point of action. Arguably none of this addresses root causes: rising levels of oxidative stress are a consequence of lower level forms of damage and change in aging. So we should expect the scope of benefits to be limited; the results of mitochondrially targeted antioxidants in flies and mice over the past decade might set the expected ballpark.
Aging is characterized by a number of physiological changes including loss of cell division, oxidative stress, DNA damage, nuclear changes, and increased expression of senescence-associated genes. It has been known for some time that oxidant stress plays a central role in the aging process, and is causally involved in the injury to cellular proteins and DNA. When reactive oxygen species (ROS) accumulation exceeds the detoxifying ability of the cell, the resulting oxidative stress induces damage, senescence, and apoptosis.
We recently reported that the Na/K-ATPase - Src - EGFR signaling pathway serves as a feed-forward amplification loop for oxidants (Na/K-ATPase oxidant amplification loop, NKAL), a signaling cascade resulting in additional ROS generation. We further showed that this NKAL is involved in various disease models ranging from uremic cardiomyopathy to obesity. Our group developed a peptide, pNaKtide, from the N domain of the Na/K-ATPase α1 subunit. This peptide binds Src kinase; ultimately inhibiting the Na/K-ATPase feed forward amplification of ROS. Based on these earlier observations, we hypothesized that the NKAL might play a role in the aging process and antagonism of this pathway by pNaKtide might attenuate the aging process.
We previously showed that a western diet (WD) induced Na/K-ATPase signaling and increased oxidative stress in mice. We used this dietary approach to investigate the effects of age and oxidative stress in adipose tissue, and heart, which are both affected by the aging processes. In both of these organ systems, old mice and old mice fed a WD had evidence for oxidant injury, which was related to the stimulation or inhibition of the NKAL with the WD or pNaKtide, respectively. In our experiments, old mice had increased fat deposition along with large adipocytes and increased TNFα levels; these changes were accentuated in the old mice fed a WD. Aging of heart tissues is associated with impaired function detectable with echocardiography and fibrosis measurable with histology. These changes were exacerbated by the WD and attenuated by pNaKtide treatment as well. Again, these changes in adipose tissues were negated with pNaKtide treatment.