A Synopsis On Aging—Theories, Mechanisms And Future Prospects Part 4

Please contact oscar.xiao@wecistanche.com for more information

(1) Caloric restriction

Contrary to what pharmaceutical companies would have you believe, there is still no way to delay aging, even faintly, and the long searched Fountain of Youth (Grene, 2010)remains elusive to this day. Yet, some of the effects of aging can be delayed. For example, skin aging can be minimized by reducing exposure to the sun(Kimlin and Guo,2012) and it has been known since the 1930s that restricting calories(caloric restriction, CR) can extend the lifespan of laboratory animals(McCay,1935). bioflavonoids Some have postulated that this is due to an increased formation of free radicals within the mitochondria, which causes a secondary induction of increased antioxidant defense capacity(Shimokawa and Trindade,2010), while others suggest that the limited availability of nutrients forces the metabolism to undergo optimization (de Magalhaes,2013). Considering observations made in mice, others believe that the genetic program maybe "slowed down", thus indirectly affecting aging (de Magalhaes and Church, 2005). Additionally, because CR also induces various alterations, both at the hormone (Kim et al,2015; Masoro et al., 1992)and at the proteome level (Baumeier et al.,2015), caloric restriction is recognized as the sole therapy capable of potentially delaying aging. In Fig. 10, simplified views of the complex metabolic pathways that regulate mammalian longevity are highlighted.

Please click here to know more

(2) Stem cell therapies

There has been a continuous and widespread buzz over stem cells in the general public and this notoriety is thoroughly deserved. These cells have been demonstrated to be a viable solution to health issues ranging from blindness(Nazari et al., 2015)and nerve regeneration (Faroniet al.,2013) to liver restoration(Christ et al,2015), as well as potential therapies in movement disorders (Mochizuki et al,2014)and other age-related illnesses, namely, muscular dystrophies(Bose and Shenoy, 2016) and skin deterioration(Peng et al.,2015). It is then not surprising that stem cells have been touted as potential treatments for the diseases of aging and for rejuvenation. Recently, Liu and co-workers reported the use of platelet-rich plasma for the recovery of stem cell senescence in SAMP8 mice(Liu et al.,2014)and postulated that rejuvenation of lineage could be achieved through the transplantation of restored stem cells in aged individuals, which could be applied in the treatment of age-related ailments. Experimental studies have also suggested that CR exerts its effect on stem cell dynamics and viability, by enhancing the preservation of a more durable population in the diverse stem cell niches of body tissues (reviewed elsewhere(Mazzoccoli et al,2014). Nonetheless, there is no direct evidence that stem cell-based anti-aging therapies will work, and, before such treatments are available, it is necessary to fully understand the mechanisms of action. Though depletion of stem cells is considered to play a role in aging, it remains largely unknown whether the decline in stem cell function during aging influences longevity (Signer Robert and Morrison Sean, 2013)and the exact comprehension of the mechanisms are still vague (Oh et al.,2014), though, in somatic stem cells, it has been suggested that mitochondrial metabolism is an important regulator in aging (Ahlqvist et al,2015). Additionally, numerous technical challenges remain. Harvesting and/or preparing stem cells remains an uncertain and laborious process （de Magalhåes，2013)and, in the case of induced pluripotent stem cells, there is the need to take pause and ascertain whether subtle differences between these and embryonic stem cells may affect both their research applications and therapeutic potential (Robinton and Daley,2012). buy cistanche Stem cell applications are very much in their infancy and there is the need to investigate further, namely, at the tissue-specific level, where variations in mechanisms and signaling pathways may yield significant exceptions in delaying the aging process.

Cistanche can anti-aging

(3)Breaking AGEs

Intervention studies have clearly demonstrated that a high intake of AGEs positively correlates with tissue damage and that it can be prevented by dietary AGEs restriction(Feng et al., 2007; Poulsen et al.,2013; Van Puyvelde et al.,2014). This is further evidenced by the low-calorie intake described in numerous studies of centenarians(Martin et al.,2013; Redman and Ravussin, 2011; Weiss and Fontana,2011). Whether the low-calorie diet itself or the AGEs content could affect aging has also been studied and, in animal models, the high levels of AGEs in the CR-high diet were shown to compete with the benefits of CR through the mechanism remained uncertain (Cai et al. 2008).

Numerous pharmacological agents have also been studied as blockers of the crosslinking reactions leading to AGEs or as blockers of their actions, such as aminoguanidine (Thornalley, 2003), benfotiamine (Stirban et al.,2006), aspirin (Urios et al.2007), metformin (Ishibashi et al.,2012)and inhibitors of the renin-angiotensin system (Zhenda et al.,2014). cistanch Among these compounds, ALT-711 has received much public attention as the next-generation anti-aging product. It acts by catalytically breaking AGE crosslinks and research has highlighted its potential in alleviating numerous age-related conditions, such as heart failure(Little et al,2005), diabetic nephropathy(Thallas-Bonke et al.,2004), type II diabetes(Freidja et al, 2012)and age-associated ventricular and vascular stiffness(Steppan et al.,2012), among others.

Nonetheless, despite the extensive research carried out, and although some of these agents are in preclinical trials, the full effects and side effects of these drugs are still unknown and it could be a long time before any of these compounds emerge as safe and efficient agents with therapeutic actions against AGES and/or their effects (Luevano-Contreras and Chapman-Novakofski, 2010).

More recently, exercise has been described as a promising avenue for the amelioration of the effects of AGEs. cistanche Australia These reports, however, are sparse, and the direction of causality between exercise tolerance and AGEs is not always clear. For example, Hartog et al.(2011)describe that breaking AGEs yields positive effects on exercise tolerance and cardiac function, but Delbin et al.(2012)postulate that the exercise itself can lead to a decrease in AGEs and, consequently, improve vascular responsiveness. As such, the interaction mechanism remains unclear, though it certainly exists and further research is required.

(4) Hormonal therapies

On the heels of the realization that patients with GH and IGF-1 deficiencies exhibit signs of early aging(Anisimov and Bartke,2013; Vanhooren and Libert,2013), growth hormone began being used as an anti-aging treatment and there is some evidence suggesting that human GH has beneficial effects in the elderly(Taub et al.,2010) and HGH supplements have been implicated in muscle mass and libido increase, as well as strengthening of the immune system (de Magalhaes,2013). Alas, similarly to many other anti-aging products, it failed to live up to the expectations, partially due to its negative side effects, such as alterations in body composition and metabolism (Carroll et al.,1998), high blood and intracranial pressure(Malozowski et al, 1993)and diabetes(Lewis et al, 2013). There are also concerns as to whether hGH could stimulate cancer, particularly in patients with existing malignant or pre-malignant tumors(Clayton et al.,2011). As such, the general consensus is that its use as an anti-aging therapeutic agent is imprudent(Liu et al, 2007). More research is needed to evaluate any possible deleterious effects and ensure its safe use as a therapeutic agent.

(5) Antioxidants

In order to fight ROS Eqs. (1)-(4)and their effects on lipids(Sharma et al.,2012), proteins (Youle and Van Der Bliek,2012), and nucleic acids(Ray et al.,2012), cells exhibit an array of endogenous antioxidant systems, further amplified by input from co-factors and by the ingestion of exogenous antioxidants(Rahman,2007). Many of these can either be synthesized or extracted and subsequently purified and then sold(de Magalhaes, 2013). cistanche benefits The most common antioxidants include vitamins A, C, and E, as well as the coenzyme Q0, the latter extensively advertised in face creams(Prahl et al.,2008), but also found to be effective in preserving mitochondrial respiratory function in aged rat skeletal (Sugiyama et al., 1995)and cardiac muscles (Park and Prolla,2005). However, some studies have revealed that antioxidants do not delay the aging process per se, but rather contribute to increasing longevity (Holloszy,1998). Vitamin C, for example, has proven to be ineffective at prolonging life-span in mice, partly because any positive benefits were offset by compensatory reductions in endogenous protection mechanisms, ultimately resulting in no net reduction of the accumulated oxidative damage(Selman et al.,2006). Despite these data, antioxidants are repeatedly hailed as miracle cures against aging and are often found in dietary supplements (Bailey et al.,2013; Wolfe and Liu,2007). The increased commercialization of these products should be worrisome, as not only large cohort studies have shown that dietary supplements do not affect mortality either positively or negatively (Park et al.2011), but have also been proven to be involved in the accelerated cancer development in mice (Sayin et al.,2014). Moreover, high-dose antioxidant supplements may in fact do more harm than good (Bjelakovic et al,2004,2008; Combet and Buckton,2014), partly due to the fact that, as previously mentioned, low levels of ROS may be beneficial and may have a positive role in life-span(Lee et al.,2010). Therefore, although low-dose mixtures of antioxidants can sometimes have a beneficial effect (Gutteridge and Halliwell,2010), it reflects mostly (if not only)in those members of populations whose diet and lifestyle result in micronutrients deficiencies (Shenkin, 2013).

Overall, there is little evidence that antioxidants have the power to delay aging and these are perhaps more suited to be used in alternative applications, such as functional ingredients in food systems to reduce oxidative changes (Samaranayaka and Li-Chan,2011)and "cosmeceuticals"(Bogdan Allemann and Baumann,2008). The intake of antioxidants should, hence, occur when, and only when, supplemented in our diet, not tablets or pills (Bjelakovic et al., 2014).

(6) Telomere-based therapies

If telomere extension can increase cell proliferative capacity in vitro(Ramunas et al.,2015)and account for the reversal of tissue degeneration in mice (Jaskelioffet al,2011), then there is the possibility of being used to attenuate the rate of aging. That is certainly the core concept behind the commercialization, by some companies, of telomere measurement kits (Wolinsky,2011), aimed at estimating the biological age of individuals and, to some extent, the risk of developing telomere shortening-associated diseases, such as atherosclerosis (Samani et al.,2001), coronary heart diseases(Ogami et al,2004)and liver cirrhosis (Wiemann et al.,2002). Nonetheless, despite the media hype (Geddes and Macrae,2015; Knight,2015; Pollack,2011), you might be better off looking at a calendar, as there is little evidence to support the claim that telomere measurement provides a better estimate of biological age than chronological age(de Magalhaes,2013). Pharmaceutical companies are, however, making efforts in developing telomerase-based therapies. One natural telomerase activator product, TA-65@, is already available (Harley et al,2011)and, although it has failed to prolong life-span, it has yielded apparent positive immune remodeling and beneficial effects on metabolic, bone, and cardiovascular health (Harley et al,2013).

However, conflicting evidence (Cheung et al,2014; Effos,198; Holliday,2014; Toda et al,1998) and the realization that mice over-expressing telomerase do not live longer (de Magalhaes and Toussaint,2004)are powerful reasons to take pause regarding such therapies. Moreover, telomerase expression has long been linked to the promotion of tumor growth and cell proliferation(Peterson et al.,2015), and, therefore, there is a justified fear that the use of telomerase activators may increase cancer development risk.

(7) Therapies to come

There are various approaches that have yielded promising initial results in delaying aging. The use of rapamycin is one such approach. This is an immunosuppressant, commonly used to prevent organ rejection (Dumont and Su,1996). Rapamycin has been demonstrated to extend maximal life-span in mammalian species, but it is not clear whether the drug slows mammalian aging or if it has an isolated effect on longevity by suppressing cancers, which is the main cause of death in mouse strains (Ehninger et al.,2014)and it has been shown to extend murine lifespan, tough exhibiting limited effects on aging (Neff et al,2013). Rapamycin works by inhibiting a complex pathway called the target of rapamycin(TOR), and, more specifically, over the mammalian target of rapamycin (mTOR), a kinase at a key signaling node that aggregates and integrates information regarding extracellular growth factor stimulation, nutrient availability and energy supplies (Ehninger et al.,2014)(Fig.10), This compound shows, nonetheless, serious side effects, such as nephrotoxicity (Murgia et al., 1996), thrombocytopenia(decrease of platelets)(Sacks, 1999), and hyperdy slipidemia (elevated levels of lipids)(Stallone et al.,2009). Consequently, different laboratories and companies are currently targeting more specific downstream nodes of this pathway, in order to develop anti-aging drugs without the side effects of rapamycin (de Magalhaes et al, 2012).

The klotho gene, which codes for one membrane protein and one secreted transcript that acts as a circulating hormone, appears to influence aging, as mutations in this gene have resulted in accelerated aging in mice, as well as low-level expression(Kuroo et al.,1997). Overexpression of klotho, in turn, extended the lifespan by about 30% (Kurosu et al.,2005). The action mechanism of this gene remains largely unknown, but evidence point to the insulin/IGF-1 signaling pathways and may also be involved in calcium metabolism and in a vitamin D endocrine system(Tsujikawa et al., 2003). Additionally, resveratrol has also been described as an inducer of klotho expression (Hsu et al.,2014). These data make the involvement of the klotho gene in aging rather plausible, though more work is necessary to confirm this claim and elucidate the mechanisms involved in this process, for this and other genes which have been implicated in the aging process(ElSharawy et al..2012: Hackl et al 2010; Klement et al.,2012; Zhong et al.,2015). Such extensive knowledge would allow for effective gene therapies, based on the modulation of these aging-related genes and, hence, extend the lifespan.

Supplementation with precursors of the oxidized form of cellular nicotinamide adenine dinucleotide(NAD+)has also been demonstrated to extend life-span and to rescue premature aging phenotypes in both nematodes (Fang Evandro et al.,2014) and mice(Scheibye-Knudsen et al.,2014; Zhang et al.,2016). Hence, strategies aiming at the conservation of cellular NAD may result in improvements in mammalian life-span, though it remains to be seen whether NADH precursor supplementation will, in effect, yield overall health benefits in aging human populations.

Perhaps the most futuristic anti-aging therapy-at least, in our collective imagination is nanotechnology, which may be due, in part, to the book in which the term was coined, Engines of Creation(Drexler, 1996), immediately evoking images of tiny, highly complex nano-machines, or nanobots, sometimes also referred to as nanites. Nanotechnology holds many promises and expectations in a wide range of applications. Nonetheless, thus far, the biomedical applications, including the nanotech fight against aging, entail a level of technological advancements that are certainly within our reach, though not yet available. The first steps into this brave new world have been taken and, recently, an intelligent system has been devised that lays the foundations for the future development of new therapies against aging. This nanodevice consists of capped silica nanoparticles that can selectively release drugs in aged human cells(Agostini et al,2012)and has enormous potential in the treatment of a myriad of diseases, namely, cancer or Alzheimer's. Hence, there is a promise that nanostructures of the like will be able to drive chemical reactions that are capable of slowing down or even reversing senescence, by reversing the chemical reactions and damage that take place with aging. Soon.

6. Conclusions

1. Biological aging, termed senescence, is one of the most complex biological processes. Theories of aging are generally classified as either program theories or damage theories. More recently, combined theories, in which the aging process is considered to a more comprehensive and global degree, have emerged, but definitive evidence is still elusive.

2. The complexity of the aging process has led to the realization that an integrative

approach is necessary to better understand the mechanisms of aging. In this regard, omics-genomics, transcriptomics, proteomics, lipidomics, and metabolomics-can play a pivotal role in the elucidation of the complex, interconnected changes that take place at the different levels of the biological hierarchy during aging, though the current knowledge of these molecular interactions is still very limited.

3. Senescence is not the inevitable fate of all organisms and it can be delayed.

In the last few decades, there has been an increase in evidence showing that aging is not an irreversible process. Additionally, we are now privy to a multitude of mechanisms that allow considerable lifespan extensions.

Most of the reported life-extension mechanisms have been observed in simpler 4.]

organisms and these have still to be demonstrated as viable anti-aging therapies in humans. Additionally, these do not curtail one of the hallmarks of aging, cognitive impairment. (5)Research into aging is blooming but biogerontologists must be aware of this interconnectivity that, not seldom, obfuscates the primary cause(s)of aging and greatly limits the ability to reach valid and definitive conclusions.

This article is extracted from Ageing Res Rev. Author manuscript; available in PMC 2018 June 07.