Life happens a long way from thermodynamic steady state. Its consistency is ceaselessly powerless by a wide gathering of inside and outside stressors, and, in these circumstances, things slope to go into disrepair rapidly aside from effectively kept up. Keeping the procedures going and reserved needs steady exertion and this is unessential as far as common determination, there are more huge activities. Along these lines, programming for presence in the long run comes up short, and it is this that results in aging (Kirkwood & Wellcome, 2005). Aging is the dynamic gathering of varieties with time related with or in charge of the consistently expanding introduction to infection and passing which run together with propelling age. These time connected varieties are portrayed to the aging process (Harman, 1981).Aging is tentatively the most natural well understood normal for human science. Each of us rapidly accomplishes learning of the maturing procedure. Relatively every normal for a life form’s phenotype encounters change with maturing, and this common multifaceted nature has driven, throughout the years, to a confounding expansion of thoughts regarding helpful cellular and sub-atomic origin.(Kirkwood & Wellcome, 2005).
Word “aging” is confusing because it can be defined by several ways. Firstly, without showing any effect to entity, only rise in calendar age. Secondly, negative, neutral or positive alternations with increasing calendar age. Thirdly, deterioration or senescence with increase in age. Aging causes diseases of late life to occur relatively earlier ,not disease itself.(Kass, 1983).Broad precise investigations on species aging and life span have demonstrated fruitful in building up numerous critical authenticities and insights about the aging process(Finch, 1994) that have still to be clarified and understood. the endeavors to clarify late-life mortality levels using evolutionary theory(Mueller & Rose, 1996) have failed until now because they required highly particular and idealistic conventions. See reviews of (Charlesworth & Partridge, 2015)(Pletcher, Curtsinger, & Url, 2012).The main problem with understanding the process of aging is its complex nature. genetic studies have now strongly shown that aging is controlled by precise genes conserved from yeast to mice(Guarente & Kenyon, 2000)
Maybe the focal conundrum of aging science is that it is concerned to comprehend a procedure that happens unanimously inside our own species (and numerous others) but then runs specifically counter to the hidden driving power of living frameworks, the energy of natural selection and choice to help and maintain life. Aging is, most importantly, about the distress of living frameworks to continue onward. Such systems don’t, in general, surrender the battle effortlessly, and we may foresee that, in figuring out how Aging dissolves what’s more, in the long run overpowers our survival instruments, we will acquire a great deal more about how these mechanisms are systematized.(Kirkwood & Wellcome, 2005).
To inquire as to why aging happens is to enter the domain of evolutionary science, which progressively apparently is important for understanding wellbeing and illness(Stearns & Koella, 2010). How aging plays out, in any case, is very confusing, and there are numerous highlights of the aging phenotype that can give an appearance of programming. In fact, some portion of the captivation of opposed pleiotropy to many, both in the area and far from the aging field, perhaps how it proposes that aging occurs for a reason. The strategy isn’t aging, in essence, yet the early advantage for which the pleiotropic trait is chosen. In this sense, it is conceivable even to consider aging to be being program driven, like growth, despite the fact that the program is developed for some other reason.(Kirkwood & Wellcome, 2005).
Once August Weismann had separated life into an unpreserved somatic and immortal germ line, the somatic line began to be viewed as non-reusable. As Weismann wrote in 1889, “the perishable and vulnerable nature of the soma was the reason why nature made no effort to endow this part of the individual with a life of unlimited length”(Rose, 1991). This quote gives rise to two theories. Each of them introduced a distinct direction of thought in gerontology. First, mortality can result from benefits at young ages (e.g., improved performance). This idea is the origin of the antagonistic pleiotropy theory later developed by (Medawar, 1952) and (Williams, 1957). Secondly ,mortality can arise from distribution of inadequate resources for reproduction. This is the cause of the allocation of resources or disposable soma theory developed by (Kirkwood & Wellcome, 2005).
Experimental data were presented to differentiate two hypotheses as early as 1917. It was made known that caloric restriction (CR) – a drop in food intake without malnutrition — extends life span and stops age-related sterility in rodents.(Osborne, Mendel, & Ferry, 1917). These data were primarily forgotten but have now been replicated several times. In 1950’s, aging started to be understood from an evolutionary standpoint. Because organisms tend to die from external causes in the wild, the odds of survival to old age is low. Therefore, the force of natural selection weakens with time of life. Natural selection, which is strong early in life, can favor antagonistically pleiotropic genes (AP genes), genes that offer aids early in life but are harmful later. By 1957, it was generally acknowledged that there were genes that are helpful early in life but cause aging phenotypes at older ages. This idea predicts that the inhibition of some genes will extend life extent, but at the cost of growth or reproduction. Research efforts were focused on gaining evidence for the “allocation of resources hypothesis”. Aging was presumed to result from the random buildup of damage, subsequent in disorder and an increase of entropy that could not be controlled or prohibited.
In 2007, some investigators declared that the problem of aging had been solved.(Hayflick, 2007). This interpretation stated that aging is just decline and functional failure due to an collection of random molecular damage from countless causes, and stubborn to efficient involvement(Hayflick, 2007). The first positive screens for genes that deferred aging began in the mid 1980’s.(Klass, 1983). In 1993, Kenyon and colleagues, also screening for long-lived C. elegans, found that mutations in the gene daf-2 increases the life span of C. elegans hermaphrodites by more than two times as compared to wild type nematodes. Afterward these findings, the yeast chromatin-associated protein Sir2 (silent information regulator-2) and its mammalian ortholog SIRT1, as well as other sirtuins, were found to increase long life in various species, ranging from yeast(Powers, Kaeberlein, Caldwell, Kennedy, & Fields, 2006) to mammals, stanching from important discoveries in Lenny Guarente’s lab(Picard et al., 2004). Sirtuins are also involved in nutrient identification, DNA damage recognizing and responses(Guarente & Kenyon, 2000), genomic stability(Picard et al., 2004), metabolic diseases, and cancer in mammals. Consequently, in 2003, it was confirmed that knocking down TOR in C. elegans increases life span more than doubles.
Aging at Molecular Level
To understand the process of aging, we must take a deep look of it at molecular level. At the molecular level, evidence proposes that several of the most important mechanisms comprise damage to macromolecules. Major theories that have been proposed to explain aging are as follows:
Somatic Mutation Theory
“The somatic mutation theory of aging postulates that the accretion of mutations in the genetic material of somatic cells as increase in time results in reduction in cellular functions. The collection of random mutations disables genes that are important for the working of the somatic cells of numerous organ systems of the person, which results in a decline in organ function. When the organ role decreases below a dangerous level, death arises”.(Varilly & Chandler, 2012).Abundant studies have stated age-related upsurges in somatic mutation and other forms of DNA damage, proposing that the capacity for DNA repair is a significant cause of the rate of aging at the cell and molecular level. There common relationship between long life and DNA repair(Promislow, 1994). This is chiefly well exemplified by studies on the enzyme poly (ADP-ribose) polymerase-1 (PARP-1), which is a main player in the abrupt cellular response to stress induced DNA injury(Bürkle, 2001)
Future Therapies of Aging
Of great attention and excitement, aging now appears to be controlled at least in part by signal-transduction pathways that can be manipulated pharmacologically. There are several Proposed Hypothesis and prototypes are available which can be used as Therapies of Aging. Additional research and advancement of instruments would lead to a better therapy of aging process. Some of proposed hypothesis and techniques are as follows
Antiaging Blood Filtration Column (AABFC) Hypothesis
In recent times, it has been revealed that inhibiting activities of several aging-related molecules or ARMs in blood decelerates aging in mice. If this situation is also applicable for humans, obstructing or enhancing such molecular activities would upsurge lifespan and combat aging-related health problems. To translate these findings into medical treatment is the basic core of the prospective hypothesis(Shahidi Bonjar & Bonjar, 2015). An “antiaging blood filtration column” (AABFC) is a probable device that would restrain ARMs from blood. The AABFC membrane would be a non-porous, organic bio-compatible polymer with about 200 μm thickness; it would be longitudinally folded and packed in the AABFC to have extended contact surfaces on both sides with the blood that would pass through it. The ARM-ABs would be engineered with the ability to reside firmly on both sides of the membrane to act as the retaining platforms to trap ARMs from the blood stream. Approximate internal volume of the column could be approximately 100 mL. Including connection tubes, at any given point of time, the total volume of blood undergoing processing would be approximately 200 mL; yet, the precise settings should be revealed through proper researches.(Shahidi Bonjar & Bonjar, 2015).Blood passes through the AABFC with the aid of a peristaltic blood pump. Pressure monitors, heparin injections, and air traps would aid in the line to provide safe and smooth circulation. Before blood enters the column and after leaving it, blood samples would be taken at certain intervals to detect ARM titers with the aid of serological examines. All tubing and the AABFC would be applied aseptically to avoid infection; but, that would be single used and would be properly disposed of after treatment.(Shahidi Bonjar & Bonjar, 2015). The proposed treatment would be efficient but AABFC treatment may cause some complications such as hypotension, muscle cramps, infection, clotting, itching, dry mouth, and anxiety. The cures are the same as those performed in hemodialysis; however, the problems would be much less in the AABFC than in patients with kidney failure taking frequent dialysis treatments.
Figure 1 Schematic diagram of proposed treatment using “antiaging blood filtration column” (AABFC) for removing aging-related molecules (ARMs) from the blood stream of middle-aged and aged people, a treatment that could reduce age-related physical deteriorations in later life.
Notes: At each treatment session, the intent would be to set the ARM titer near to youth homeostasis. The AABFC would work aseptically with the aid of a blood pump in a closed circuit. Main tools of the treatment would include: (A) the hand of a person to be treated; (B) blood removed from an artery through tubing; (C) an arterial pressure monitor; (D) a peristaltic blood pump; (E) a heparin pump (to prevent clotting); (F) an inflow pressure monitor; (G) an inflow sampling port to detect ARM titer before processing; and (H) an AABFC, the central device to immobilize ARMs from blood. The AABFC bears a longitudinally folded biocompatible membrane impregnated with ARM antibodies (ARM-ABs) on both sides. ARM-ABs would conjugate with ARM antigens; hence, the ARM-ABs would be trapped inside the column. Components would also include (I) an outflow sampling port to detect ARM titer after processing; (J) a venous pressure monitor; (K) an air detector and air trap; and (L) processed blood returns into the vein. All tubes and the AABFC would be applied aseptically; however, both tubing and the AABFC are single-use and would be appropriately disposed of after treatment.
Modulation of Telomerase Binding Proteins
Both the double- and single-stranded telomeric DNA are bound and protected by DNA-binding proteins that in turn associate with other signaling proteins ⁄ complexes to achieve telomere end protection and length control(Imbert, Botto, Farra, & Domloge, 2012). The telomere binding proteins TRF1, TRF2, POT1, RAP1, TIN2, and TPP1 form a complex known as the telosome, or shelterin complex, which is crucial for telomere role, telomere maintenance, and associations with intracellular signaling pathways (Liu, O’Connor, Qin, & Songyang, 2004). Human TRF1 and TRF2 differ from each other at their amino terminus, which comprises an acidic region in TRF1 and a basic region in TRF2. The basic amino terminal domain of TRF2 is important for binding of the double-strand ⁄ single-strand DNA junction and for the supercoiling of telomeric DNA, and it may regulate the formation and stabilization of the T-loop structure(van Overbeek & de Lange, 2006). TRF2 also recruits a variety of other DNA damage sensing and DNA repair proteins to the telomere, such as Apollo(van Overbeek & de Lange, 2006), the DNA repair MRN complex(Zhu, Küster, Mann, Petrini, & De Lange, 2000), Ku70 ⁄ Ku86(Song, Jung, Jung, Lee, & Lee, 2000), and PARP1.(Gomez, 2006). Compounds capable of maintaining the functionality of telomere binding proteins should prevent telomere shortening and limit the number of cells entering in senescence. Senescent cells, while in a nondividing state, remain biologically active but display a change in their gene expression profile toward a more catabolic and proinflammatory phenotype degrading the tissue microenvironment (Millis, Sottile, Hoyle, Mann, & Diemer, 1989). In addition to the simple termination of cell division, an age-related buildup of senescent cells has the potential to disturb tissue homeostasis and underlie age-related diseases and cancer.(Imbert et al., 2012) As little is known about the expression of telomere binding proteins in human skin, and the modulation of their expression with aging, it remains an interesting field of skin research and a key area for future anti-aging developments(Imbert et al., 2012).
Therapeutic Strategy of Telomerase Activation
Even though cancer and aging have been studied as independent diseases, escalating evidence suggests that cancer is an aging-associated disease and that cancer and aging share many molecular pathways. Recent studies confirmed telomerase activation as a latent therapeutic target for age-related diseases (Bernardes de Jesus & Blasco, 2013). Different scientist studied the effect of enforced expression of telomerase in mice and its effects on aging and cancer.
The finding that telomerase has roles in distinct and complementary circuitries has helped reveal its function in cancer and aging. Indeed, a change of paradigm seems to be occurring in telomerase biology, with a switch from viewing telomerase as fueling cancer to reversing aging.(Imbert et al., 2012)
Prototype Antiaging Drugs
Although Different drugs are now used for the antiaging process but there is still needing to be improvement of these drugs and discovery of new antiaging drugs. One of the most common drug is Metformin. Metformin is an antidiabetic drug which is now under trial foe use as antiaging drug. It has been studied that chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice(Anisimov et al., 2008).Therefore it has a great potential for its use as antiaging drug.
Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age-associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti-cancer treatment, and rapamycin is already approved for use in human patients(Kaeberlein, 2010). Rapamycin extends life span in mice, when administered to genetically heterogeneous mice from the age of both 9 months(Moskalev & Shaposhnikov, 2010) and 20 months(Harrison et al., 2009).
Senolytic agents are testing in proof of concept clinical experimentations. To do so, new clinical trial patterns for testing senolytics and other agents that target important aging mechanisms are being developed, because use of long-term endpoints such as lifespan is not feasible. These strategies include testing effects on melancholic, accelerated aging-like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time(Kirkland, Tchkonia, Zhu, Niedernhofer, & Robbins, 2017).