This open access review of the mechanisms of aging is a followup of sorts to the noted Hallmarks of Aging paper, in which researchers followed the SENS model of breaking down aging into a set of actionable causes. There is some overlap between the SENS view of molecular damage and the Hallmarks view of metabolic dysregulation - cellular senescence is noted in both, for example - but from a SENS perspective the Hallmarks list includes a lot of things that are either markers of damage or later consequences of damage, not causes of aging. This well illustrates what has long been a major challenge in aging research, which is that cellular biochemistry is so very complex that there is still plenty of room to argue over whether important mechanisms in aging and age-related disease are causes or consequences of one another.
Getting the relationships right is vital to the development of life-extending therapies, as only the treatment of causes will prove to be very effective - and as things stand most of the field is working on patching over consequences instead, a strategy doomed to be both expensive and produce only marginal benefits. The only way to settle these debates over cause and consequence any time soon is to produce rejuvenation therapies that actually work, which is one of many reasons why advocacy for SENS research and development is so important. Sadly, in this paper as elsewhere, the ambitions with regard to aging and longevity are small: giving a greater priority to adjusting diet and lifestyle is the primary conclusion found at the end, and we all know just how little that can achieve in the grand scheme of things. No lifestyle will give you more than very tiny odds of reaching a century of aging, and no lifestyle choice can prevent you from aging and declining along the way. Only biotechnology that addresses the causes of aging can do more.
The human superorganism (i.e., the host and its microbiome) is a complex metabolic system in which nutrient intake, physical activity, and elimination of waste orchestrate anabolic and catabolic reactions that ultimately determine development, maturation, and aging. After many years of being subordinate to the surge in cellular and molecular biology, the study of metabolism is now experiencing its own Renaissance. A clear understanding is emerging of the key roles that metabolites play in all biological processes, including physiological and pathological aging.
We have previously classified the nine candidate hallmarks of aging into three categories. The primary hallmarks (genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis) are the main causes of molecular damage underlying aging. The antagonistic hallmarks (deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence) mediate beneficial effects at low levels and protect the organism from damage and nutrient scarcity but become deleterious at high levels. Finally, the integrative hallmarks (stem cell exhaustion and altered intercellular communication) are the culprits of aging and arise when the accumulating damage cannot be compensated by homeostatic mechanisms. All these denominators of aging have important repercussions on cellular metabolism. Here, we describe the links between each hallmark of aging and metabolic perturbations, discuss current strategies to manipulate metabolism for increasing healthspan and lifespan, and elaborate on the major threat posed to public health in the developed world, i.e., the incipient "westernization" of lifestyle.
Aging complicates the maintenance of cellular and organismal metabolic homeostasis, hence favoring an imbalance in metabolic landscape that self-amplifies and eventually becomes clinically manifest. Thus, anti-aging interventions such as calorie restriction may operate in the context of a metabolic reprogramming that (1) ensures efficient nutrient utilization and (2) enhances stress resistance. Although such a metabolic reprogramming may be extremely broad and hence difficult to modulate pharmacologically, it may be subjected to some unifying principles. In particular, the signal-transduction cascades and metabolic circuitries rewired in the course of aging may operate in the context of a limited number of modules that redistribute nutrients and other resources from anabolism to non-toxic catabolism, hence favoring homeostasis preservation.
Our current knowledge on the metabolic manipulations that may improve health in the elderly and hence extend longevity are still in their infancy, although there is no doubt that a combination of regular exercise and appropriate diet can delay the onset and progression of all the hallmarks of aging. Formulating dietary recommendations is complicated, and personalized advice from a nutritionist may be recommendable in some situations. Nonetheless, we surmise that an increase in food-free intervals, a reduction in overall caloric and animal protein intake, as well as a general shift from health-compromising food to a Mediterranean diet rich in fibers and complex carbohydrates may have sizeable anti-aging effects, especially when combined with regular physical activity.