The Mechanisms of Dietary Restriction and Aging: A Detailed Exploration (Part 1)

Part 1 discusses theories in mitigating oxidative stress and reduced Insulin/IGF-1 signaling. In part 2, we delve into enhanced AMP-activated Protein Kinase and reduced mTOR1 signalling.

Dietary restriction, more commonly known as calorie restriction or a reduced intake of food without malnutrition, has been closely linked to extending the lifespan of multiple species, ranging from yeast to mammals. Scientists have explored the effects of this dietary regimen for nearly a century, and two key theories have arisen to explain its impact on ageing: the mitigation of oxidative stress and reduced Insulin/IGF-1 signalling. These theories, although illuminating, are punctuated with puzzling paradoxes, underscoring the complex relationship between nutrition, metabolism, and the ageing process. This review aims to provide a detailed discussion of these theories, focusing on the role of mitochondria, reactive oxygen species (ROS), and hormonal signalling pathways.

Mitochondria, Oxidative Stress, and Ageing

The mitochondrion is an organelle present within our cells, often referred to as the "powerhouse of the cell." It uses a process called oxidative phosphorylation to generate ATP, the primary energy source for cellular functions. However, this energetic process is not without its downsides. Oxidative phosphorylation produces reactive oxygen species (ROS), molecules that can cause cellular damage if they accumulate excessively, a phenomenon associated with ageing. This notion led to the free radical theory of ageing, proposed by Dr. Denham Harman, suggesting that the accumulation of ROS is a significant contributor to the ageing process. This theory was later refined into the oxidative stress theory of ageing, which encompasses all forms of ROS.

The free radical theory of aging, introduced by Dr. Denham Harman in 1956, posits that the process of aerobic respiration leads to the production of free radicals. Over time, these free radicals can cause cumulative oxidative damage to cells, contributing to the natural aging process.

Interestingly, dietary restriction appears to reduce the accumulation of ROS, effectively minimizing oxidative damage. This phenomenon has been observed in many animal models, including mice and even humans participating in the Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE) trial. Yet, contrary to what one might expect, some studies have shown an increase in lifespan even when ROS levels are elevated, suggesting that ROS might also have beneficial roles. This apparent contradiction introduced the concept of mitohormesis, where low levels of ROS are thought to act as signaling molecules, enhancing cellular defenses.

The balance between ROS production and clearance, oxidative damage, and subsequent repair is complex, and the relationship between oxidative stress and ageing is still not fully understood. The theory that dietary restriction extends lifespan simply by reducing oxidative stress has been questioned, indicating that other factors may also be involved.

Reduced Insulin/IGF-1 Signalling

The insulin/insulin-like growth factor-1 (IGF-1) signalling pathway, conserved from worms to humans, is another major player in longevity regulation. Insulin and IGF-1 are crucial for maintaining physiological homeostasis, regulating energy metabolism and growth processes. Reducing the activity of this signalling pathway has been shown to extend the lifespan of various organisms, from the worm Caenorhabditis elegans to fruit flies and mice.

In C. elegans, for instance, a mutation in the 'daf-2' gene - an ortholog of the mammalian insulin/IGF-1 receptor gene - resulted in a more than two-fold lifespan extension. This pathway, when downregulated, promotes the activities of specific transcription factors, such as FOXO, which in turn modulate the expression of genes associated with stress response and metabolism.

The link between dietary restriction and reduced insulin/IGF-1 signalling presents a tantalizing explanation for the beneficial effects of dietary restriction. For instance, dwarf mice with reduced GH/insulin/IGF-1 signalling display enhanced lifespan, similar to that observed under dietary restriction.

However, reduced insulin/IGF-1 signalling is not necessarily beneficial. In humans, defects in insulin signalling are associated with insulin resistance and type 2 diabetes, while defects in growth hormone (GH)/IGF-1 signalling are linked to impaired growth and an increased risk of cardiovascular diseases. Thus, the overall balance of insulin/IGF-1 signalling seems to be crucial for optimal health and longevity.

Insulin Sensitivity, Ageing and Dietary Restriction

Insulin sensitivity, the measure of how effectively cells respond to insulin, is another aspect that has been closely linked to ageing. Insulin resistance, characterized by a reduced cellular response to insulin, is a hallmark of type 2 diabetes, a disease that is more prevalent among the elderly. Interestingly, centenarians and their offspring have been found to display enhanced insulin sensitivity and reduced risk of type 2 diabetes, suggesting a correlation between insulin sensitivity and longevity.

Although dietary restriction has been linked to increased insulin sensitivity, some long-lived mutants, such as mice lacking insulin receptor substrate 1 (IRS1) or those with brain-specific reduction in IRS2, exhibit insulin resistance, challenging the belief that enhanced insulin sensitivity is a necessary condition for lifespan extension.

Conclusion

The relationship between dietary restriction, ageing, and longevity is far from straightforward. The mechanisms underlying the lifespan-extending effects of dietary restriction involve intricate cellular processes, from mitochondrial function and oxidative stress to hormonal signalling. Although substantial progress has been made, many questions remain unanswered. Further research is warranted to elucidate the finer details of these processes, and perhaps someday we will be able to develop interventions that can mimic the beneficial effects of dietary restriction without the need to substantially reduce our food intake.

In the meantime, a balanced diet coupled with regular exercise is the best bet for promoting healthy ageing. It is essential to remember that while we cannot avoid ageing, how we age is to a large extent within our control. Although the exact mechanisms by which dietary restriction influences longevity are not yet clear, the connection is evident, emphasizing the importance of diet in determining not just how long we live, but also how well.