Biomedicines in Longevity and Aging The Quest to Resist Biological Decline

Aging may be considered a side effect from years of biological insults, lifestyle and inherited genetic traits, along with biological limitations such as stem cell exhaustion, telomere attrition, epigenetic drift, immune senescence, oxidative stress, genomic replicative errors, arterial calcification, osteoporosis, neurological decline and much more. Heterochronic parabiosis was the first experiment that demonstrated that a restoration of function in some tissues could transpire in vivo which appeared to ameliorate/counteract aging, where older mice would appear to become more youthful again simply by sharing circulatory systems and receiving the blood of younger mice [ 1 , 2 ]. Aging could be associated with a gradual loss of homeostatic mechanisms that maintain the structure and function of adult tissues, particularly the nervous system. Cellular insults such as ultraviolet light, lack of essential coenzymes such as nicotinamide adenine dinucleotide (NAD) or reduced levels of the body's antioxidants such as glutathione [ 3 ], the three super oxide dismutases [ 4 , 5 ] loss of mitochondrial function unable to power the cell efficiently [ 6 ], including mutations in the genetic code itself [ 7 ] all eventually come back to plague human biology in the form of age-related pathologies. So, could restoring those cellular factors back to youthful levels prevent the onset of the pathologies they would otherwise generate? One of the hallmarks of cellular aging is an accumulation of damaged macromolecules such as deoxyribose nucleic acid (DNA), proteins, and lipids [ 8 ]. These become chemically modified by reactive molecules such as free radicals that are generated during normal cellular metabolism and increase with age due to decreasing levels of the body's natural anti-oxidants [ 9 ]. Even epigenetic dysfunction or genomic instability due to molecular events resulting in tumourigenesis from carcinogenic environmental pathways can deliver a disease or early mortality. Inadequate lifestyle choices speed up the effect of age-related pathologies such as genomic instability and cellular dysfunction that induce the onset of age-related disease [ 10 ]. The goal of this paper is to demonstrate that interventions exist to resist biological decline as shown below in Fig. 1 . Multiple drivers certainly exist in the aging process, and it appears that no single molecule will ever be able to fully control aging due to the heterogeneity and complexity of aging itself; it is much more conceivable that because there are multiple drivers of aging that this will be confronted with a multifaceted approach in order to deliver humanity into an extended health span with the possibility of an extended life span. Some of the most well-studied gene families shown to influence longevity, either through antiaging or pro-aging effects, are the insulin receptor signalling pathway [ 11 , 12 ], FOXO family of transcription factors [ 13 – 15 ], Sirtuins [ 16 , 17 ], and mechanistic target of rapamycin (mTOR) [ 18 , 19 ]. This paper will discuss nine known drivers of the aging process and how those pathways may be controlled or influenced with non-invasive techniques to possibly ward off age related decline. Various drivers of aging may overlap; however, for the purposes of this review they have been separated and treated as their own single condition, so the rejuvenation is clear for the purposes of this discussion.

Cell division causes the telomeric caps of chromosomes to shorten during replication [ 30 ]. It has been demonstrated that the shorter telomeres become the more cellular dysfunction may ensue, so an inference could be drawn that telomere length is also an indicator for cellular health [ 31 ]. Moreover, if telomeres become excessively short cells can no longer divide, at which point cells should enter apoptosis. However some cells may not follow apoptosis and may enter a state known as senescence [ 32 ]. The divisional limits on cells from telomere length is known as the Hayflick limit [ 33 ]. Telomere attrition was first discovered by Nobel Laureates Elizabeth Blackburn, Jack Szostak and Carol Greider [ 34 ]. An enzyme known as telomerase can prevent further loss of telomeres [ 35 ]. Telomerase activity was found to be higher in peripheral blood mononuclear cells and was shown to decline with the onset of aging [ 36 , 37 ], and supplementation of telomerase via oral or intranasal would not be successful due to stomach acids, immunogenicity (adaptive and innate), microbiome breakdown of small molecules in the stomach, and the lack of cell surface and nuclear transporters to deliver such a large enzyme into the nucleus. Telomerase remains active in regenerative tissues and in cancer cells, though is downregulated in most of the somatic tissues [ 38 ]. This active state of telomerase in cancer cells means that cancer cells remain immortal, as these cells never reach a divisional limit [ 38 ]. However, new biomedicines are being developed and peptides have become a front runner for the elongation of telomeres, with Epithalon (also known as epitalon) inducing the expression of telomerase catalytic subunit and associated enzymatic activity [ 39 ]. Epithalon is a relatively small tetrapeptide with an alanine > glutamic acid > aspartic acid > glycine (Ala-Glu-Asp-Gly) sequence. Epithalon is also shown to regulate the pineal gland, retina and brain, and also induces neuronal cell differentiation in retinal and periodontal ligament stem cells [ 39 , 40 ]. Furthermore, a polyamine known as spermidine is also another interesting target for the prevention of telomere attrition. In a study where spermidine was administered to promote autophagy in mice, it was also found that spermidine increased telomere length [ 41 ]. Other compounds also exist to resist telomere attrition such as ergothioneine, and cycloastragenol which is an aglycone of Astragaloside [ 42 , 43 ]. Side by side comparisons have also been performed for other compounds by Tsoukalas et al that showed the effects of various telomerase activators (from most potent to least potent) being Centella asiatica extract formulation, oleanolic acid, an Astragalus extract formulation, TA-65 containing Astragalus Membranaceus extract and maslinic acid [ 44 ] Human trials are warranted for further confirmation on the efficacy of the aforementioned telomerase activators. Studies that only show results in vitro or model organisms should not be considered results that will convey over to humans as such molecules (if orally administered) must survive the first pass effect and also evade immunogenicity and the microbiome [ 45 ]. Currently the easiest way to increase telomere health is exercise [ 46 ]. The importance of maintaining cellular populations is paramount, as fewer cells concludes fewer proteins for tissues or enzymatic rejuvenation functions. Much more research is necessary in the fight against telomere attrition.

The human body contains (on average) 37 trillion cells [ 52 ]. Each cell contains a complex network of organelles that perform functions which are imperative for (most notably) cellular energy, maintenance, differentiation and replication of genetic information and genomic stability. These trillions of cells also produce free radicals whilst carrying out a myriad of essential functions. NAD is a primary regulator in cellular and genomic health, and therefore could be considered a master regulator in aging [ 53 ]. NAD is critical in the production of adenosine triphosphate for cellular energy production. NAD is also paramount in DNA repair machinery such as Poly (ADP-ribose) polymerase 1 (PARP1) [ 54 ]. PARP1 is a nuclear enzyme found in the DNA repair pathway. The effect of the PARP1 mechanism is to repair single or double strand breaks from being copied or joined incorrectly. However, PARP1 requires sufficient levels of NAD to function efficiently, and when NAD levels are low PARP1 can no longer perform its function which may result in missense variants being replicated that may lead to cancer. When NAD levels decline, cells cannot function aptly, and this may be a potential birthplace of where some disease may stem from. Glucose metabolism, cardiovascular function, stem cell health, neural function are all regulated by NAD levels [ 31 ]. Rajman et al. have effectively demonstrated how important NAD is in restoring communication between the cell nucleus and mitochondria. These declining NAD levels are easily attenuated during age with over-the-counter NAD precursors. NAD trials are now delivering datasets with conditions such as psoriasis and skeletal muscle activity showing promising results along with inducing a transcriptomic signature and suppressed inflammatory cytokines [ 55 , 56 ]. Endogenous antioxidants also diminish throughout age. Notably glutathione, the three super oxide dismutases (SOD1, SOD2 and SOD3) and catalase which could be regarded as the body's primary biomedicines, are all major players in the fight against free radicals and the pathophysiology of aging [ 2 ]. Whether this decreasing of the body's antioxidants is a result of the aging process or a driver of the aging process remains to be seen, yet much of these endogenous antioxidants can be restored with simple supplementation. Again, it is observed that a relatively simple approach can restore youthful levels of essential biological mechanisms to ward off the aging process. Methods of delivery such as oral, intranasal, transdermal patches or IV drip are still matters of contention, though the evidence shows that consumers can safely use some oral products to reclaim their ability to fight against free radical damage [ 32 ]. Glutathione that is administrated orally is poorly absorbed due to its swift hydrolysis by γ-glutamyltransferase existing in intestinal mucosa, hepatocytes and cholangiocytes [ 57 ]. N-acetylcysteine (NAC) has become a well-known precursor in raising glutathione levels, though human trial data on the best dosage and delivery methods are lacking [ 58 ]. Super oxide dismutase is found in three distinct regions. SOD1 is cytoplasmic, whilst SOD2 is mitochondrial and SOD3 is extracellular [ 59 ]. It should be noted that reactive oxygen species also increase with age creating a disbalance between oxidants and anti-oxidants [ 60 ].

The process of non-enzymatic changes to lipids and proteins once exposed to monosaccharides is known as glycation [ 67 ]. These monosaccharides interrupt or disrupt various signalling processes so that the cell cannot receive or send signals efficiently. This can lead to improper or total lack of cell function, cell death or cell senescence. Glycation can have a flow on effect onto proteins in different cell types including liver, eyes, heart, and brain. An excessive level of glycation can result in a plethora of pathophysiologies. Sugary food and drinks are absorbed by the body and these monosaccharides then cause reactions known as 'advanced glycation end products (AGEs) [ 68 ]. However, the accumulation of AGEs can be controlled with low glycaemic foods [ 69 ]. Building muscle requires glucose resulting in the cleaning up and removal of AGEs [ 70 ]. Antioxidants are also a defence mechanism against AGEs, and healthy diets rich in fruit and vegetables could be considered the first line of defence. Cheese contains high levels of AGEs and vegetable fats contain fewer AGEs than animal fats. Concentrated fatty dairy foods such as creams and butter can also contain high levels of AGEs [ 71 ]. The accumulation of AGEs is greatly affected by the choices of the individual. Many studies are available that demonstrate clear data in humans regarding the deleterious effect that AGEs produce [ 71 ]. Diet is clearly the primary damage mechanism from AGEs. Mammalian Target of Rapamycin (mTOR) mTOR inhibitors are a class of drugs designed to block the mTOR signalling and growth pathway. This class of drugs shows great promise with suppressing tumour growth and aging [ 72 ]. Metformin and Rapamycin are both common drugs used for the treatment of diabetes; however recent data indicates that they may possess longevity benefits by suppressing the mTOR pathway. mTOR is a kinase which acts upstream of autophagy which degrades and recycles damaged molecules and organelles. mTOR is a protein involved in cell cycle progression and regulation, and therefore drives cells to divide, including cancer. Inhibiting the mTOR pathway with signalling suppressors such as Metformin or Rapamycin will prevent further signalling, which then prevents further cell division, which in turn may prolong the time for healthy cells to reach their divisional limit [ 73 ]. Metformin is also a fasting mimetic which assists the body with the effects of a fasting diet [ 74 ]. This holds additional value due to starvation mechanisms activating under calorie restriction, and furthermore, the body may begin to eliminate various cells from tissues [ 75 ]. These cells are usually cells that have become of low level importance or dysfunctional. Other biological products such as stored glucose may also be recycled via the kidney which regulates glucose via gluconeogenesis by taking glucose from the circulation and then using the glomerular filtrate to reabsorb the glucose [ 76 , 77 ]. Metformin is also well tolerated in humans and has been used to deliver anti-diabetic properties since the 1950's [ 78 ]. Metformin's major competitor in the antiaging biomedicine race is Rapamycin, which has been shown to extend the lives of short-lived mutant strain mice by up to three-fold [ 79 ], and in 2006 was acclaimed to be an anti-aging biomedicine that could be used immediately to slow the onset of aging and disease [ 80 ]. Both Metformin and Rapamycin are well tolerated in humans with a good history of relative safety when used properly, however recent data indicates that Rapamycin may induce Alzheimer's beta-amyloid plaques in mice, and further research is required before any definitive conclusion in humans can be reached [ 81 ]. 2.6.1. Inflammation Inflammation is a signalling mechanism which evolved to communicate to certain cell types to either fight infection or repair injury. This mechanistic pathway utilises proinflammatory cytokines which transiently assist repair mechanisms [ 82 ]. Once repair function has transpired pro-inflammatory cytokines disappear until another infection or injury signals to them. However, it has been observed that during aging these proinflammatory cytokines begin to linger in the blood for extended periods which interfere with numerous healthy tissue functions. Pro-inflammatory cytokines have been connected to blood vessel damage, depression and even arthritis by interfering with stem cell pathways and it should be noted that cytokines are part of the senescence-associated secretory phenotype (SASP) found across all cell types including postmitotic cells [ 83 , 84 ]. Improper diet is now thought to be a major cause of extended inflammation with various foods delivering excessive amounts of Omega 6 fatty acids. Small amounts of Omega 6 have not been shown to be harmful, however the high levels of Omega 6 in certain food products may be harmful to those that are at high risk of inflammation [ 85 ]. Furthermore, it should be noted that AGEs a

Multiple pathways clearly exist in human aging, and as those aging corridors are becoming better understood, innovative techniques or therapies are also being found or designed to overcome them. This paper does not cover every facet of aging or an exhaustive list of the biomedicines to overcome the drivers of aging, though it does find that various biomedicines now exist to help regulate facets of the aging process. The literature reviewed in this paper clearly finds a trend that science may be starting to influence how humanity may age. The biosciences are now delivering not only insights into the major causes of aging, but also how to attenuate some of those aging pathways to fend off biological decline to extend health-span and lifespan. This discussion simply demonstrates that novel biomedicines and treatments already exist to attenuate some of the biological drivers of aging. The benefits for civilization to go beyond a good healthy diet and exercise, but to actively resist facets of aging with therapies such as the ones discussed here are vast. Keeping society out of hospitals, delivering a longer period for our species to be fit and healthy and preventing poor quality of life or disease is no longer a futuristic vision, but a vision that is close to humanity's grasp. Not only can considerable sums of government healthcare spending be saved by ensuring society is kept healthy, but vast human wealth can be generated by keeping the general population fit, vibrant and able to contribute.