Aging is a process resulting from the accumulation of multiple changes occurring in cells and tissues leading to a progressive decline of physiological function and responsible for an increased risk of disease and death (see “Aging Mechanisms”). Antiaging strategies are interventions intended to slow the aging process and prolong life span.
A number of theories have been proposed with the thrusting aim to explain the aging process (see “Aging Theories”). They substantially fall in two main categories based on different concepts of aging (Libertini 2015).
For the first interpretation, aging (i) is the cumulative result of various degenerative processes, (ii) is not adaptive (i.e., it is opposed by natural selection), and (iii) is not a consequence of specific mechanisms genetically determined and regulated.
For the second interpretation, aging (i) is evolutionarily advantageous (i.e., it is adaptive and favored by supra-individual natural selection in particular ecological conditions) and (ii) is a consequence of specific mechanisms genetically determined and modulated. These differences in interpretation require equally diverse strategies aimed to restrain or block aging manifestations. It is therefore essential to contemplate and expose these strategies in two different sections.
However, there is a common category of phenomena that needs a preliminary mention. In fact, it is known that certain substances and certain unhealthy habits accelerate the timing of aging manifestations. For example, diabetes, obesity, dyslipidemia, hypertension, smoking, and alcohol abuse (all conditions mainly dependent on unhealthy habits and here defined as “risk factors”) appear to anticipate pathological changes that are generally associated with advanced age such as endothelial dysfunction; age-related macular degeneration; Alzheimer’s disease (AD) and Parkinson’s disease (PD); hearing and olfactory impairment; emphysema; osteoporosis; atrophy of the skin, testis, muscles, and stomach; cardiac and renal insufficiency; and many others. On the contrary, avoiding or limiting the abovementioned unhealthy habits and using particular types of drugs such as statins, ACE inhibitors, and angiotensin receptor blockers (all considered here as “protective factors”) are able to counteract or restrain the occurrence of the same pathological changes. It is good to point out that risk factors appear to cause an abnormal acceleration of aging process, while protective factors counteract such acceleration. However, granted that protective factors restore the normal rhythm of aging process, there is no study showing that it is slowed or blocked by them. A healthy lifestyle and avoiding harmful substances can prevent premature aging and even allow the achievement of the famous “100 years of life,” but they do not appear to modify the normal rhythm of aging or prevent senescence, whatever is the adaptive or nonadaptive cause (or causes) of aging. So, in the next exposition, the very useful advice of dodging risk factors, which would allow to have a “physiological” aging, will not considered as an antiaging method. Only the means that could be able to slow down or even block or reverse physiological aging will be discussed.
It should also be noted that in modern countries, the lengthening of the average life expectancy is a result of (i) reduction of infant mortality, (ii) reduction of mortality due to accidental causes, and (iii) the treatment of the effects of unhealthy lifestyles through medical actions, while, on the contrary, it is not at all a consequence of the slowing down of physiological aging rhythms. For antiaging strategies correctly understood in this restricted sense, after an era in which the problem was considered without possible solutions, now such strategies begin to be formulated and considered as possible.
Key Research Findings
Antiaging Strategies According to the Hypothesis of Non-programmed Aging
Notably, the aging is seen as a set of degenerative processes, rather than a distinct entity, and even the term “aging” is usually used to summarize the overall effects of heterogeneous phenomena (Libertini et al. 2017). Many theories have been proposed to explain the process of aging, but none of them appears to be totally satisfactory. In the “old paradigm” of aging, some traditional theories are included. Such theories, also referred to as non-programmed, assert that aging is neither an adaptive nor a genetically programmed phenomenon but it is the result of an organism’s inability to contrast natural deteriorative processes by opposing itself to selective pressures (Libertini et al. 2017) (see “Non-programmed (Non-adaptive) Aging Theories”).
Generally, the aforementioned paradigm includes all non-evolutionary and a large part of the evolutionary theories, according to which aging is determined by accumulation of various types of assaults that gradually induce cumulative cell damage and consequent fitness impairments. Among the different theories proposed, “the damage or error theory,” “the mutation accumulation theory,” “the antagonistic pleiotropy theory,” and “the disposable soma theory” are the best known (Libertini 2015). In turn, the damage or error theory provides for (1) wear and tear theory, (2) living theory, (3) free radical theory (FRTA), (4) somatic mutation theory, and (5) theory of error catastrophe. Each of them focuses on a different environmental factor able to harm the whole organism, but all examine how continuous injuries will eventually lead to impairments and dysfunction (Jin 2010) (see “Mitochondrial ROS Aging Theory”).
Among the abovementioned aging theories, the FRTA has been considered one of the most important for more than five decades and supported by thousands of scientific publications per year.
The FRTA, proposed by Harman in the 1956, states that organisms age since they accumulate reactive species, both derived by oxygen (ROS) and nitric oxide (RNS) that are harmful practically for all the cellular constituents (Harman 1956). ROS, that include both free radicals such as superoxide (O2−), hydroxyl (OH), and non-radical species, such as hydrogen peroxide (H2O2), are continuously generated as products of the normal cellular metabolism. ROS are able to damage proteins, membranes, and nucleic acids because of their energy instability due to the presence of at least one unpaired electron on their surface, which makes them highly reactive. To achieve a more stable energy state, they tend to surrender their own electron or acquire another electron, thereby making a new unstable molecule, which in turn will react with another molecule, thus initiating a chain reaction leading to further formation of toxic metabolites.
The continuous action of free radicals is fulfilled especially in the early aging and has been associated with the onset of cancer, cardiovascular diseases (CVD) and respiratory pathologies, diabetes, multiple sclerosis, rheumatoid arthritis, and neurodegenerative diseases, including PD and AD (Phaniendra et al. 2015; Conti et al. 2015). To counteract the negative effects caused by ROS accumulation, thereby contrasting the development of an imbalance between prooxidant and antioxidant molecules, referred to as oxidative stress, mammalian cells activate a complex series of nonenzymatic and enzymatic molecules known as antioxidants, including vitamin C, vitamin A, alpha-lipoic acid, thioredoxin, coenzyme Q, beta carotenoids, alpha-tocopherols, as well as superoxide dismutase (SOD), catalase (Cat), glutathione peroxidases, reductases, and s-transferases (Ighodaro and Akinloye 2017; Conti et al. 2016).
Oxidative stress is strongly associated with aging and aged-associated diseases. Consequentially, strategies aiming at reducing oxidative stress might be recognized as “antiaging strategies.” In this context, the use of antioxidant supplementation has deserved attention as valuable therapeutic intervention (Forte et al. 2016; Corbi et al. 2016). Importantly, the interaction between endogenous and exogenous antioxidants with the global cellular redox status is very complex and represents a relevant issue still under debate in the scientific community (Afanas’ev 2010).
Harman’s theory is supported by numerous experiments, although many others oppose his assumption. In particular, some authors contest the universal role of ROS in aging, contemplating a broader concept whereby different forms of damage serve as causal factors in the senescence process in which the ROS buildup is one of the major causes, but not the only one (Gladyshev 2014).
Although in some animal models antioxidant proteins extend life span, their over-expression could be ineffective and even harmful in humans. Likewise, it has been demonstrated that none of SOD deletion mutants of C. elegans exhibited a shortened life span despite increased sensitivity to oxidative stress, in contrast to what observed in other species such as yeast, flies, and mice, where loss of either cytoplasmic or mitochondrial enzyme resulted in decreased life span. Furthermore, surprisingly, SOD-2 mutant worms even those with deletion of SOD genes could live longer than wild-type worms (Van Raamsdonk and Hekimi 2009). In humans, numerous clinical trials, often showing conflicting results, have led to hazardous misconception on the use of antioxidant supplementation in the treatment of aging-related diseases (Conti et al. 2016; Forte et al. 2016).
Notably, the FRTA suggests a linear dose-response relationship between increasing amounts of ROS and biological damage, potentially culminating in the development of morbidity and mortality. Based on this assumption, the oxidative stress is the main driving force of aging and a crucial determinant of life span, but today, a modernized view of Harman’s hypothesis, the so-called mitohormesis, is taken into account (Ristow and Schmeisser 2014). Originally, hormesis was defined as a phenomenon in which small amounts of harmful substances (e.g., ionizing radiation, heavy metals, and toxins) have positive stimulatory effects on living organisms (Luckey 1982). Today, hormesis is recognized as an adaptive response of cells and organisms to moderate and/or intermittent insults derived, for example, from an exposure to prooxidant or pro-inflammatory substances (Calabrese et al. 2007). According to this principle, low or moderate levels of ROS or other potentially harmful molecules induce a positive biological response, while a large amount of them likely cause detrimental effects.
Studies on sirtuin mechanisms have gained much interest in the past years, emphasizing the critical importance of these enzymes in human pathophysiology. Sirtuins, mainly the best-characterized Sirt-1, Sirt-3, and Sirt-6, regulate a wide range of processes, such as metabolism, inflammation, DNA repair, stress resistance, and aging. They deacetylate substrates very important in the control of bioenergetics and metabolism, such as peroxisome proliferators-activated receptor-γ (PPAR-γ) and its coactivator-1α (PGC-1α) and AMP-activated protein kinase (AMPK), and involved in oxidative stress and inflammation, such as Forkhead box O transcription factors (FOXOs), and NF-κB (Corbi et al. 2012b).
Both CR and ET might be able to increase ROS production with a concomitantly induction of an adaptive response exemplifying by upregulation of the antioxidant defense, thereby stimulating a health-promoting adaptation (Russomanno et al. 2017). With these premises, the regulation and not the simple suppression of oxidative stress and/or other cellular injuries might be valuable antiaging strategies.
CR is more than a simple limitation of calories for maintenance of body weight. It is the drastic curtailment of calorie intake (up to 50% in some cases) without incurring malnutrition. In fact, eating less is a valid health support not only for obese people but also for those who are in good physical condition. Protective effects of CR on cardiovascular and neurodegenerative diseases have been investigated firstly in animal models and then in humans.
The CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) was the first study designed as a randomized clinical trial. It has been conducted in two phases to investigate the effects of long-term CR in humans and to test the adaptive changes that had been demonstrated in rodents subjected to CR. The CALERIE Phase 1 consisted of three single-site pilot short-term (6–12 months) randomized studies, whose data were used for the Phase 2 study design. In the CALERIE Phase 2 trial, young and middle-aged (men aged 21–50 y and women aged 21–47 y) nonobese (body mass index [BMI], 22.0 ≤ BMI < 28.0 kg/m2) adults were enrolled and randomly assigned to either 25% CR intervention or ad libitum (AL) diet control group.
In 2015, Ravussin and collaborators demonstrated that sustained CR was feasible, tolerable, and safe. Individuals did not experience adverse effects; a temporary metabolic adaptation was found in CR, while no significant difference on core temperature was observed between CR and AL groups. In addition, T3 and tumor necrosis factor-α levels resulted decreased in CR group, who had also larger decreases in cardiometabolic risk factors (Ravussin et al. 2015).
In the following years, additional and secondary data analyses based on CALERIE dataset have been carried out. Procedures, protocols, and published articles are currently available online (Calerie Research Network, https://calerie.duke.edu). Reduction of energy intake is one of the most successful non-pharmacological interventions for increasing life span in a wide variety of organisms, slowing the rate of aging and postponing the onset of age-associated pathologies such as CVD, AD and PD, cancer, and type 2 diabetes. However, the molecular mechanisms underlying the antiaging effect of CR have not yet been fully clarified and are thought to imply the activation of multiple survival mechanisms evolutionarily conserved to protect organisms from the stress. There is a growing body of evidence suggesting that CR alters and promotes expression of proteins involved in cellular repair, autophagy and protein turnover, production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-6 (IL-6), and resistance to stress and glucose metabolism (Testa et al. 2014).
Actually, it is difficult to conduct CR protocols in humans because the subjects must be kept in a state of hunger and the duration of this state necessary to achieve a clinically significant effect is still unknown. Thus, researchers are trying to develop molecules that mimic the metabolic, hormonal, and physiological effects of CR without altering dietary intake. These compounds, called CR mimetics (CRM), activate stress-response pathways, as observed in CR, and protect against a variety of stressors. The CRMs include some polyphenols, especially the well-known Sirt-1 activator resveratrol, rapamycin, and rapalogs (inhibitors of mammalian target of rapamycin, mTOR), α-lipoic acid, 2-deoxy-d-glucose and other glycolytic inhibitors, and drugs such as metformin and thiazolidinediones. All these interventions modulate autophagy and pathways responsible for aging/longevity, such as sirtuins, AMPK, TOR, and insulin-like growth factor (IGF-1) signaling (Price et al. 2016).
Another strategy useful in delaying aging is ET. Compelling evidence has reported that it can improve quality of life, prevent the development of chronic disease, and increase life expectancy. People who perform regular physical activity have up to a reduced risk of developing CVD, stroke, diabetes obesity, and some cancers (e.g., colon and breast cancers), as well as musculoskeletal disorders (i.e., osteoporosis, osteoarthritis, and sarcopenia). ET, as integral part of cardiac rehabilitation, is recommended in the international guidelines for treatment of patients with coronary artery disease and heart failure (HF). A well-structured ET unquestionably ameliorates cardiac symptoms and improves exercise tolerance and cardiorespiratory fitness and reduces depression and anxiety.
Unfortunately, despite the well-documented beneficial effects, cardiac rehabilitation remains an underutilized therapeutic approach, and its effects on all-cause and cardiac mortality continue to be under debate. Indeed, its hemodynamic and biochemical benefits are widely known, but the underlying mechanisms have not been fully clarified. ET generally enhances ROS production, but at the same time leads to the upregulation of several antioxidant enzymes, including SOD, Cat, and GPx, and prevents senescence (Russomanno et al. 2017).
ET is an effective health intervention also in the prevention of type 2 diabetes, in the treatment of chronic obstructive pulmonary disease (COPD), and in other chronic pathologies, such as back pain and osteoarthritis. Its benefits on symptoms and quality of life are very relevant. In the clinical practice, ET protocols vary in type (aerobic, anaerobic, and mixed aerobic/anaerobic), intensity/workload (endurance, resistance, and strength), and clinical setting (hospital−/center- and home-based) and are recommended for patients who have no comorbidities limiting exercise capacity. Moderate exercise should be promoted and personalized in older people, especially regarding a preventive approach for successful aging (Fossel 2004).
Antiaging Strategies According to the Hypothesis of Programmed Aging
If aging is a programmed phenomenon, this necessarily requires the existence of specific determinant mechanisms (see “Programmed (Adaptive) Aging Theories”). In this regard, among the various explanations proposed, there is the so-called telomere theory (Fossel 2004) or also subtelomere-telomere theory (Libertini et al. 2018), which will be the only one considered here because it appears to be the most supported by the evidence (see “Telomere-Subtelomere-Telomerase system”). A brief exposition of this theory is necessary as a premise before exposing possible antiaging strategies.
Cells are subject to continuous turnover, that is, they are physiologically subjected to various types of programmed cell death (e.g., detachment of cells from mucosae of body cavities, keratinization of hair and epidermis cells, apoptosis) and are continually replaced by other elements produced by division of appropriate stem cells. Cell reproduction necessarily involves the replication of their DNA molecules, but these are incompletely duplicated by the enzyme DNA-polymerase, i.e., a part of the ends of the DNA molecules, the telomeres, is not duplicated (Olovnikov 1971). There is however an enzyme, the telomerase, which allows to restore the part of DNA not duplicated.
When this enzyme is repressed, the telomere is shortening at each duplication cycle. Risk factors and protective factors appear to act by accelerating or reducing, respectively, the rhythms of cell turnover with analogous actions on telomere shortening. As the telomere shortens, a heterochromatinic hood that covers the telomere slides over the part of DNA adjacent to the telomere, defined as subtelomere, with two important effects. The first (gradual cell senescence) is the progressive alteration of cellular functions, including extracellular secretions, with negative consequences both for the affected cell and for other nearby and even distant cells as a consequence of these alterations (Fossel 2004). The second effect is the increasing probability of activation of the cell senescence program (Blackburn 2000). When this important cellular program is activated, the cell replication capacity is blocked (replicative senescence), and the manifestations of the gradual cell senescence are shown at the highest level.
For perennial cells (e.g., most neurons), there is no cell turnover, and therefore no direct effect due to telomere shortening is possible, but these cells are dependent on other cells that are subject to turnover. The impairment of these cells, consequent to telomere shortening, results in secondary impairment of perennial cells (Libertini and Ferrara 2016a). Furthermore, telomere shortening determines an increased risk of cancer (DePinho 2000).
- (b)Periodic activation of telomerase by techniques that use modified viruses. The method that appears to be clearly more effective and feasible is telomerase activation by telomerase reverse transcriptase (TRT) introduced into a single cell or in an organism using as carrier a modified adenovirus.
It is well known since 1998 that telomerase activation is able to completely reverse the manifestations of cell senescence (Bodnar et al. 1998).
In fibroblasts aged in vitro and showing “substantial alterations in gene expression,” telomerase was activated. Afterward, the functionality of the fibroblasts was “assessed by incorporation into reconstituted human skin”: this skin showed no biochemical or biological difference with that obtained using young fibroblasts (Funk et al. 2000).
In old mice where telomerase was artificially blocked, telomerase reactivation determined a clear reversal of aging manifestations, even for the nervous system (Jaskelioff et al. 2011).
In 1- and 2-year-old mice, telomerase activation through adenoviruses carrying the mouse TRT, delayed aging, and increased life span. The increase in life span was of 24 and 13%, respectively (Bernardes de Jesus et al. 2012).
An important concern about telomerase reactivation is that this might increase the risk of cancer. This fear is based on the hypothesis that the known mechanisms that limit the ability of cell duplication would be a general defense against cancer. However, this hypothesis is opposed by a series of empirical evidence and theoretical arguments (Fossel 2004; Libertini 2009; Mitteldorf 2013; Libertini and Ferrara 2016a). Moreover, in the abovementioned experiment in which telomerase was activated in old mice, the increase in longevity was not associated with an increased risk of cancer (Bernardes de Jesus et al. 2012).
- (c)Elimination of senescent cells
This method is discussed in more detail in the entry Senolytic drugs and in a recent paper (Libertini et al. 2018) (see “Senolytic Drugs”). In short, the aim of this approach is the elimination of senescent cells (i.e., cells in which the cell senescence program was activated) and consequently the damaging effects caused by such cells. Various substances are being tested, and their efficacy appears to be particularly considerable for some aging manifestations. The predictable limit of this method is that it would not allow counteracting the progressive depletion of stem cells and the progressive slowing of cell turnover (Libertini et al. 2018).
- (d)Reversion of the cell senescence state
This possible method for the treatment of aging alterations originates from the thesis that senescence is caused by alterations of the epigenetic regulation (López-León and Goya 2017), a possibility that is compatible with telomere theory (Libertini et al. 2018). Therefore, aging manifestations could be opposed by the reprogramming of senescent cells to a condition equivalent to that of pluripotent stem cells, for example, by temporary reactivation of the so-called Yamanaka factors (Takahashi and Yamanaka 2016; Mendelsohn et al. 2017). In Hutchinson-Gilford progeria syndrome mice, the activation of some Yamanaka factors ameliorated “aging-like phenotypes,” but, in wild-type mice artificially aged by exposition to specific toxins, the same activation caused transient effects conceivably due to other mechanisms (Mendelsohn et al. 2017).
- (e)Modifications of the subtelomere associated with periodic telomerase activation
A more radical approach hypothesizes, in conjunction with periodic stimulations of telomerase enzyme, the insertion of a neutral sequence between telomere and subtelomere in order to delay the progressive subtelomere repression. By this approach, if applied from a non-advanced age, it would be theoretically possible to have an indefinite lengthening of life. It should be noted, however, that the method would imply a modification of the human genome with all the possible reservations and objections of various types that this would arouse (Libertini and Ferrara 2016b).
Given the high complexity of the aging process, none of the aging theories postulated until now are exhaustive. It is very difficult to operate a clear separation among the different hypothesis whose classification is actually very hard. As a consequence of such complexity, the research of reliable antiaging strategies is very difficult. Antiaging strategies should be applied at different levels in consideration of the main concepts of programmed and non-programmed aging. If the aging is a non-programmed process, the regulation and not the simple suppression of oxidative stress and/or other cellular injuries could be effective. In this context, it is crucial to stress the importance of personalized approach that take into account the individual specific metabolic demand and genetic background, mainly in the elderly. Based on the hypothesis of programmed aging, mainly the “telomere theory,” strategies aiming at activating telomerase, eliminating senescent cells, and/or reverting cellular senescence could be practicable. Doubtless, there is a need to better clarify the molecular mechanisms underlying the aging process in order to promote interventions able to delay or even contrast the age-associated conditions.
- Afanas’ev I (2010) Signaling and damaging functions of free radicals in aging – free radical theory, hormesis, and TOR. Aging Dis 1(2):75–88Google Scholar
- Calabrese EJ, Bachmann KA, Bailer AJ et al (2007) Biological stress response terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 222(1):122–128. https://doi.org/10.1016/j.taap.2007.02.015CrossRefGoogle Scholar
- Fossel MB (2004) Cells, aging and human disease. Oxford University Press, New YorkGoogle Scholar
- Fossel MB (2015) The telomerase revolution. BenBella Books, DallasGoogle Scholar
- Jin K (2010) Modern biological theories of aging. Aging Dis 1(2):72–74Google Scholar
- Libertini G (2009) The role of telomere-telomerase system in age-related fitness decline, a tameable process. In: Mancini L (ed) Telomeres: function, shortening and lengthening. Nova Science Publishers, New York, pp 77–132Google Scholar
- Libertini G, Rengo G, Ferrara N (2017) Aging and aging theories. JGG 65:59–77Google Scholar
- Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Biochem 201:394–397Google Scholar
- Ristow M, Schmeisser K (2014) Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response 12:288–341. https://doi.org/10.2203/dose-response.13-035.RistowCrossRefGoogle Scholar
- Sohal RS, Forster MJ (2014) Caloric restriction and the aging process: a critique. Free Radic Biol Med 73:366–382. https://doi.org/10.1016/j.freeradbiomed.2014.05.015CrossRefGoogle Scholar