Further Development 5.1: A Chapter on Senescence and Longevity

Stem Cells: Their Potential and Their Niches

The hydrozoan cnidarian Turritopsis dohrnii appears to be able to cheat death, earning it the nickname “the immortal jellyfish.” It is one of a handful of cnidarian species known to be capable of reverting to an essentially embryonic state after having reached its adult form (the sexual medusa; see Figure 9). What roles stem cells may play in this reverse development and whether such processes might be applicable to human organs remains to be seen, but it is interesting to know that such organisms exist.

Longevity and Senescence

There is no single hypothesis that explains aging and senescence. Mutations in genes encoding DNA repair enzymes and factors regulating metabolic rates may be crucial in aging. The insulin signaling cascade (involving the interplay of metabolism and diet) mediates between fertility and aging. In addition, random epigenetic changes in DNA and chromatin can inactivate genes as one ages. New research suggests that stem cells and their niches are critical for normal organismal function and that as mutations and epigenetic changes accumulate, these stem cells may die or become nonfunctional. As cells become senescent, they have been seen to secrete paracrine factors that mimic inflammatory responses and suppress organ function.

Entropy always wins. A multicellular organism is able to develop and maintain its identity for only so long before deterioration prevails over synthesis and the organism ages. Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility. The characteristics of aging—as distinguished from diseases of aging, such as cancer and heart disease—affect all the individuals of a species. The aging process has two major facets. The first is simply how long an organism lives; the second concerns the physiological deterioration, or senescence, that characterizes old age. These topics are often viewed as being interrelated. Both aging and senescence have genetic and environmental components, and so far there is no unified theory of aging that puts them all together. As one review (Underwood 2015) noted, “In the race to find a biological clock, there are plenty of contenders.”

Species-specific aging

“Death,” according to Steve Jobs (2005), “is very likely the single best invention of life.” But it is obvious that death occurs differently in different organisms and that these differences are inherited. A mouse can live for 3 years; humans can live for decades. The maximum lifespan is the maximum number of years an individual of a given species has been known to survive and is characteristic of that species (Coles 2004). The maximum verified human life span stands at 122.5 years. The life spans of some tortoises and lake trout are uncertain but are estimated to extend beyond 150 years. The maximum life span of a domestic dog is about 20 years, and that of a laboratory mouse is 4.5 years; most mice in the wild do not live to celebrate even their first birthdays. If a fruit fly survives to eclose (in the wild, more than 90% die as larvae), it has a maximum life span of 3 months.

Genetic factors play roles in determining longevity both between and within species (Wilson et al. 2007). Most people cannot expect to live 122 years. Life expectancy—the average length of time a given individual of a given species can expect to live—is not characteristic of species but of populations. It is sometimes defined as the age at which half the population still survives. A baby born in England during the 1780s could expect to live to be 35 years old. In Massachusetts during that same time, life expectancy was 28 years. These ages represent the normal range of human life expectancy for most of the human race throughout recorded history (Arking 1998). Even today, in some countries (Angola, Chad, Lesetho, and several others) life expectancy is only around 45 years. Males in the United States today have a life expectancy of about 76 years, and females can expect to live around 81 years.1

Given that in most times and places people did not live much past the age of 40, our awareness of human aging is relatively new. In 1900, 50% of Americans were dead before the age of 60; a 70-year-old person was exceptional in 1900 but is commonplace today. People in 1900 did not have the “luxury” of dying from heart attacks or cancers, because these conditions are most likely to affect people over 50. Rather, many people died (as they are still dying in large parts of the world) from microbial and viral infections. Until recently, relatively few people exhibited the general human senescent phenotype: gray hair, sagging and wrinkling skin, arthritic joints, osteoporosis (loss of bone calcium), loss of muscle fibers and muscular strength, memory loss, eyesight deterioration, and slowed sexual responsiveness. As the melancholy Jacques notes in Shakespeare’s As You Like It, those who did survive to senescence left the world “sans teeth, sans eyes, sans taste, sans everything.”

Species-specific life spans appear to be determined by genes that effect a trade-off between the energy used for early growth and reproduction (which results in somatic damage) versus the energy allocated for maintenance and repair. In other words, aging results from natural selection operating more strongly on early survival and reproduction than on having a vigorous post-reproductive life. Molecular evidence indicates that certain genetic components of longevity are conserved between species—flies, worms, mammals, and even yeast all appear to use the same set of genes to promote survival and longevity (see Vijg and Campisi 2008; Kenyon 2010). Four sets of genes are well known to be involved in aging and its prevention, and each set appears to be conserved between phyla and even kingdoms. These are the genes encoding (1) DNA repair enzymes, (2) proteins of the insulin signaling pathway, (3) proteins in the mTORC1 signaling pathway (a cascade that regulates translation), and (4) chromatin remodeling enzymes.

DNA repair enzymes

DNA repair enzymes appear be critically important in preventing senescence (Gorbunova et al. 2007). Individuals of species whose cells have more efficient DNA repair enzymes live longer (Figure 1; Hart and Setlow 1974; MacRae et al 2015). Certain premature aging syndromes, called progerias, in humans and mice appear to be caused by mutations that prevent the functioning of DNA repair enzymes (Figure 1B; Sun et al. 1998; Shen and Loeb 2001; de Boer et al. 2002).

A after R. Hart and R. B. Setlow. 1974. Proc Natl Acad Sci USA 71: 2169–2173; B © Associated Press

Figure 1 Life span and the aging phenotype. (A) Correlation between life span and the ability of fibroblasts to repair DNA in various mammalian species. Repair capacity is represented in autoradiography by the number of grains from radioactive thymidine per cell nucleus. Note that the y-axis (life span) is logarithmic. (B) Hutchinson-Gilford progeria. Although they are not yet 8 years old, these children have a phenotype similar to that of an aged person. The hair loss, fat distribution, and skin transparency are characteristic of the normal aging pattern as seen in elderly adults. The mutation causes an aberrant nuclear envelope protein that appears to prevent DNA repair (Coppedè and Migliore 2010).

“Wear-and-tear” theories of aging are among the oldest hypotheses proposed to account for the human senescent phenotype (Weismann 1891; Medawar 1952). As one gets older, small traumas to the body and its genome build up. At the molecular level, the number of point mutations increases with age, and the efficiency of the enzymes encoded by our genes decreases (Singh et al. 2001; Bailey et al. 2004; Rossi et al. 2007). Moreover, if mutations occur in the genes encoding transcriptional or translational proteins, the cell may make an even greater number of faulty proteins (Orgel 1963; Murray and Holliday 1981; Kamileri et al. 2012).

Reactive Oxygen Species Two major sources of mutation are radiation and reactive oxygen species (ROS). The ROS produced by normal metabolism can oxidize and damage cell membranes, proteins, and nucleic acids. Some 2–3% of the oxygen atoms taken up by our mitochondria are reduced insufficiently and form ROS: superoxide ions, hydroxyl (“free”) radicals, and hydrogen peroxide. Evidence that ROS molecules are critical in the aging process includes observations that fruit flies and nematodes overexpressing the enzymes that destroy ROS (catalase and superoxide dismutase) live significantly longer than do control animals (Orr and Sohal 1994; Parkes et al. 1998; Sun and Tower 1999; Feng et al. 2001). However, these correlations have not held up in some other studies, so the genetic ability to destroy free oxygen radicals may not be essential for a long life (Pérez et al. 2009; van Raamsdonk and Hekimi 2012).

The reactive oxygen species hypothesis for aging postulates that (1) senescence results from the accumulation of DNA, lipid, and protein damage inflicted by ROS of mitochondrial origin; and (2) mitochondria of long-lived species should produce less ROS than do mitochondria of short-lived species. The results have been equivocal. Perhaps the capacity of mitochondria to consume ROS might distinguish long-lived species from short-lived species, rather than differences in ROS generation. This might be the case in the famous naked mole rat (Muro et al 2019). The naked mole rat has a maximum lifespan of about 30 years, compared to most mice, which can live to about 4 years. Although both laboratory mice and naked mole rats appear to produce similar amounts of ROS, the capacity of the naked mole rat skeletal and heart muscles to break down ROS was 2−5 times greater than that of the mice. Therefore, the ability to detoxify ROS may contribute to their longer lifespan.

Telomerase and P53 Most normal cells respond to cancer-causing stimuli by undergoing cellular senescence, a state of arrested proliferation and diminished differentiated function. Cellular senescence may have evolved to protect organisms against cancer. Instead of dividing out of control, the cells die. Cellular senescence appears to be regulated by several tumor suppressor genes, especially p53. Transcription factor p53 is thought to suppress tumorigenesis by causing cell arrest and senescence in response to short telomeres, DNA damage, and viral or external signals to divide (Gambino et al 2013; Fischer 2019).

Indeed, p53 is one of the most important regulators of cell division. This factor can stop the cell cycle, cause cellular senescence in rapidly dividing cells, instruct genes to initiate cellular apoptosis, and activate DNA repair enzymes. In most cells, p53 is bound to a repressor protein that keeps p53 inactive. However, ultraviolet radiation, oxidative stress, and other factors that cause DNA damage will separate p53 from its repressor, allowing it to function. The induction of apoptosis or cellular senescence by p53 can be beneficial (when destroying cancer cells) or deleterious (when destroying, say, neurons or stem cells).

One of the chief ways of activating p53 (and related proteins, such as p63) is to damage the telomeres, the protective nucleoprotein caps on the tips of the chromosomes (similar to the aglets on the tips of shoelaces that keep them from unwinding). When p53 is activated by damaged telomeres, DNA replication halts, and if the repair doesn’t work, apoptosis is initiated. If the cell is a stem cell or some other rapidly replicating cell, this will reduce the numbers of cells produced, and the lack of stem cells will produce an “aged” phenotype. The relationship between shortened telomeres and stem cell depletion has been seen in degenerative diseases such as mouse muscular dystrophy (Sacco et al. 2010).

There is a positive correlation between telomere length and longevity in humans (Atzmon et al. 2010; Laberthonnière et al 2019), and telomeres appear to shorten with age in the stem cell compartments of mice and humans (Zhang and Ju 2010). The enzyme complex that maintains telomere integrity is telomerase, which acts as an antisenescence complex. Mice and humans with telomerase deficiencies age prematurely (Mitchell et al. 1999). Overexpressing telomerase or reactivating it in senescent cells extends longevity in mice without increasing cancer (Tomás-Loba et al. 2008; Jaskelioff et al. 2011; Bernardes de Jesus et al. 2012). However, except for the rare genetic telomere syndromes, telomere length only gives a statistical probability of age; it does not predict the lifespan of an individual (Blackburn et al. 2015).

Aging and the insulin signaling cascade

One criticism of the idea that there are genetic “programs” for aging asks how evolution could have selected for them. Once an organism has passed reproductive age and raised its offspring to sexual maturity, it becomes “an excrescence on the tree of life” (Rostand 1962); natural selection presumably cannot act on traits that affect an organism only after it has reproduced. But “How can evolution select for a way and time to degenerate?” may be the wrong question. Evolution probably can’t select for such traits. The right question may be, “How can evolution select for phenotypes that postpone reproduction or sexual maturity?” There is often a trade-off between reproduction and maintenance, and in many species reproduction and senescence are closely linked.

Recent studies of mice, Caenorhabditis elegans, and Drosophila suggest that there is a conserved genetic pathway that regulates aging and that it can indeed be selected for. This pathway involves the response to insulin and insulin-like growth factors. In C. elegans, a larva proceeds through four larval stages, after which it becomes an adult. If the nematodes are overcrowded or if there is insufficient food, the larva can enter a metabolically dormant dauer larva stage, a nonfeeding state of diapause, a condition in which development and aging are suspended. The nematode can remain in the dauer stage for up to 6 months (rather than becoming an adult that lives only a few weeks). In this state it has increased resistance to oxygen radicals that can crosslink proteins and destroy DNA. The pathway that regulates both dauer larva formation and longevity has been identified as the insulin signaling pathway (Kimura et al. 1997; Guarente and Kenyon 2000; Gerisch et al. 2001; Pierce et al. 2001).

In C. elegans, favorable environments signal activation of the insulin receptor homologue DAF-2, and this receptor stimulates the onset of adulthood (Figure 2A). Poor environments fail to activate the DAF-2 receptor, and dauer formation ensues. While severe loss-of-function alleles in the insulin signaling pathway cause the formation of dauer larvae in any environment, weak mutations in the pathway enable the animals to reach adulthood and live four times longer than wild-type animals.

Figure 2 A possible pathway for regulating longevity. In each case, the insulin signaling pathway inhibits the synthesis of the Foxo transcription factor proteins that would otherwise increase cellular longevity<

Downregulation of the insulin signaling pathway has several other functions. First, it appears to influence metabolism, decreasing mitochondrial electron transport. Second, when the DAF-2 receptor is not active, cells increase the production of enzymes that prevent oxidative damage, as well as DNA repair enzymes (Honda and Honda 1999; Tran et al. 2002). Third, this lack of insulin signaling decreases fertility (Gems et al. 1998). This increase in DNA synthetic enzymes and in enzymes that protect against ROS is due to the Foxo/DAF-16 transcription factor. This Forkhead-type transcription factor is inhibited by the insulin receptor (DAF-2) signal. When that signal is absent, Foxo/DAF-16 can function, and this factor promotes longevity in ways not yet deciphered. It is possible that Foxo/DAF-16 activates the expression of genes involved in producing anti-stress proteins within the cell as well as lipid signals that help extend life to those cells nearby (Zhang et al. 2013). The Foxo transcription factor has been associated with longevity throughout the animal kingdom. Indeed, it has recently been shown to be one of the major drivers of stem cell renewal in potentially immortal hydras (Boehm et al. 2012).

It is possible that this system also operates in mammals, but the mammalian insulin and insulin-like growth factor pathways are so integrated with embryonic development and adult metabolism that mutations often have numerous and deleterious effects (such as diabetes or Donahue syndrome). However, there is evidence that the insulin signaling pathway does affect life span in mammals (Figure 2B). Dog breeds with low levels of insulin-like growth factor 1 (IGF-1) live longer than breeds with higher levels of this factor. Mice with loss-of-function mutations of the insulin signaling pathway live longer than their wild-type littermates (see Partridge and Gems 2002; Blüher et al. 2003; Kurosu et al. 2005). Holzenberger and colleagues (2003) found that mice heterozygous for the insulin receptor IGF-1R not only lived about 30% longer than their wild-type littermates, they also had greater resistance to oxidative stress. In addition, mice lacking one copy of their IGF-1R gene lived about 25% longer than wild-type mice.

The insulin signaling pathway also appears to regulate life span in Drosophila (Figure 2C). Flies with weak loss-of-function mutations of the insulin receptor gene or genes in the insulin signaling pathway live nearly 85% longer than wild-type flies (Clancy et al. 2001; Tatar et al. 2001). These long-lived mutants are sterile, and their metabolism resembles that of flies that are in diapause (Kenyon 2001). The insulin receptor in Drosophila is thought to regulate a Forkhead transcription factor (dFoxo) similar to the Foxo/DAF-16 protein of C. elegans. When the Drosophila dFoxo gene is activated in the fat body, it can lengthen the fly’s life span (Giannakou et al. 2004; Hwangbo et al. 2004). From an evolutionary point of view, the insulin pathway may mediate a trade-off between reproduction and survival/maintenance. Many (although not all) of the long-lived mutants have reduced fertility. Thus, it is interesting that another longevity signal originates in the gonad. When the germline cells are removed from C. elegans, the worms live longer. The germline stem cells produce a substance that blocks the effects of a longevity-inducing steroid hormone (Hsin and Kenyon 1999; Gerisch et al. 2001; Shen et al. 2012).

Calorie restriction is another way of downregulating the insulin pathway (Kenyon 2001; Roth et al. 2002; Holzenberger et al. 2003). Calorie restriction may reduce levels of IGF-1 (the main ligand of IGF-1R) and of circulating insulin, although other mechanisms are also being explored (e.g., Selman et al. 2009). Studies in primates (including humans) have not concluded that low calorie intake extends their longevity, although it does appear to retard the age-associated decline of heartbeat variability and motor coordination (see Colman et al. 2009; Mattison et al. 2012; Stein et al. 2012).

The mTORC1 pathway

One of the main ways by which the insulin signaling pathway might function to lower longevity is to activate mTORC1, a protein kinase complex that promotes the translation of mRNA into proteins in response to nutrients and hormones (Lamming et al. 2012; Johnson et al. 2013). Thus, the insulin signaling pathway depresses Foxo and at the same time activates mTORC1. Dietary restriction reduces mTORC1 activity, and mice with reduced mTORC1 levels had longer lives, better protection against age-related cognitive dysfunction, and more functional stem cells than control mice (Chen et al. 2009; Harrison 2009; Halloran et al. 2012; Majumder et al. 2012; Yilmaz et al. 2012). Reducing mTORC1 also increases the amount of autophagy, the removal and replacement of damaged organelles and senescent cells. Many of the maladies associated with old age appear to be the result of failed autophagy and replacement (Baker et al. 2011). The mechanisms by which reduced mTORC1 accomplishes these feats are still unknown, and this pathway is an area of active study.

Chromatin modification

Chromatin modification may be very important in aging. The sirtuin genes, which encode histone deacetylation (chromatin-silencing) enzymes, have been found to prevent aging throughout the eukaryotic kingdoms, including in yeasts and mammals (Howitz et al. 2003; Oberdoerffer et al. 2008). Sirtuins prevent genes from being expressed at the wrong times and places, and they help repair chromatin breaks. When DNA strands break (as inevitably happens as the body ages), sirtuin proteins are called on to fix them and cannot attend to their usual functions. Thus, genes that are usually silenced become active as the cells age.

Sirtuins accomplish this removal of acetyl groups from histones by breaking down the metabolic regulator NAD+. In this way, metabolic control and gene regulation may be coupled. NAD+ levels in the cell decline with age, and this might affect the ability of the sirtuins to function. Such declining sirtuin activity would be likely to contribute to age-associated functional declines and diseases (Imai and Guarente 2016). These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging.

Alternatively, there are other areas of the body, such as the brain, where histone deacetylases can generate an aging phenotype. Cognitive decline, especially in the ability to recall past experiences, is a normal part of the mammalian aging syndrome. Long-term memories are stabilized by chromatin remodeling in the hippocampus and frontal lobes of the brain, a process involving DNA methylation and histone modifications (Swank et al. 2001; Korzus 2004; Miller et al. 2008; Penner et al. 2011). Peleg and colleagues (2010) have shown that the normal transcription associated with long-term memory stabilization is disrupted as mice age, and that this lack of transcription is associated with lessened H4K12 acetylation. Indeed, this ability to store memory can be retrieved by infusing into the hippocampus an inhibitor of histone deacetylase (Figure 3).

After S. Peleg. et al. 2010. Science 328: 753–756.

Figure 3 Age-related memory decline in mice can be reversed by inhibitors of histone deacetylases. Mice were either unstressed (control) or stressed to form a new memory. (A) H4K12 identified by chromatin immunoprecipitation (ChIP) assays in the coding regions of three genes. The stressed mice treated with the inhibitor of histone deacetylase (SAHA) had the highest level of H4K12. (B) The stressed mice treated with SAHA also had the highest levels of expression of Fmn2 and Prkca, two genes that have been associated with memory formation. (C) Mice that were stressed stabilized a memory of this stress better if they had been treated with the inhibitor of histone deacetylases.

Random Epigenetic Drift

The idea that random epigenetic drift inactivates important genes without any particular environmental cue gives rise to an entirely new hypothesis of aging. Instead of randomly accumulated mutations—which might be due to specific mutagens—we are at the mercy of chance accumulations of errors made by the DNA-methylating and DNA-demethylating enzymes. Indeed, unlike the DNA polymerases, our DNA-methylating enzymes are prone to errors. At each round of DNA replication, DNA methyltransferases must methylate the appropriate cytosines while leaving other cytosines unmethylated, and they are not the most fastidious of enzymes, making errors at the rate of 2–4% (Ushijima et al. 2005). Within certain genetic parameters (which may affect the speed at which methylation changes occur, and which may differ between species and individuals), our cells may accumulate errors of gene expression throughout our lives.

Random epigenetic drift may have profound effects on our physiology. For instance, methylation of the promoter regions of the  and  estrogen receptors is known to increase linearly with age (Figure 4; Issa et al. 1994), and such methylation is thought to bring about the inactivation of these genes in the smooth muscle cells of blood vessels. This decline in estrogen receptors would prevent estrogen from maintaining the elasticity of these muscles, thereby leading to “hardening of the arteries.” Increased methylation of the estrogen receptor genes is even more prominent in the atherosclerotic plaques that occlude the blood vessels (Figure 5); these plaques show more methylation of estrogen receptor genes than do the surrounding tissues (Post et al. 1999; Kim et al. 2007). Thus, methylation-associated inactivation of the estrogen receptor genes in these cells may play a role in the age-related deterioration of the vascular system. This potentially reversible defect may provide a new target for intervention in heart disease. Several neurological diseases, including bipolar disorder, depression, and stress responses, have been linked to DNA methylation and/or histone modifications (Sweatt 2013). Recent studies of Alzheimer’s disease (and its mouse model) showed epigenetic signals (chromatin methylation and acetylation) indicating a loss of synaptic plasticity functions and a gain of immune function in the hippocampus. These strongly implicate the immune system (and inflammation) in predisposing people to Alzheimer’s dementia (Gjoneska et al. 2015).

After J.-P. Issa et al. 1994. Nat Genet 7: 536–540.

Figure 4 Methylation of a  estrogen receptor gene occurs as a function of normal physiological aging.

After J. Kim et al. 2007. Biochim Biophys Acta 1772: 72–80.

Figure 5 Methylation of the estrogen receptor gene in atherosclerotic plaques and adjacent nonplaque blood vessel tissue in the ascending aorta (AA), common carotid artery (CCA), and femoral artery (FA).

Horvath (2013) extended and refined the epigenetic aging clock by widescale genomic investigations of more than 50 healthy individuals at different ages. He was able to analyze over 350 sites of possible DNA methylation, showing that as people age, these sites become progressively more methylated. Cells removed from early embryos have hardly any methylation at these sites, while cells taken from centenarians are heavily methylated. Using cells from a person’s saliva, Horvath’s analysis of DNA methylation allows prediction of a person’s age to within 2 years (Figure 6). Moreover, Hannum and colleagues (2013) showed that tumors of breast, kidney, and lung tissues had more heavily methylated DNA than surrounding nontumor tissues, causing them to appear about 40% “older” than the patients from whom they were removed. This could be due to the methylation of a gene involved with the chromatin remodeling processes.

After S. Horvath. 2013. Benome Biol 15: R115/CC BY 2.0.

Figure 6 Chronological age (y-axis) of a person versus his or her DNA methylation “age” (x-axis). Each point corresponds to a DNA methylation sample taken from cells in the saliva (A) or cells in the blood (B).

As it became possible to look at DNA methylation differences in individual cells, another variable emerged. As people age, their methylation patterns get more heterogeneous. There is more cell-to-cell variability in older people than in younger people. Moreover, analysis of methylation heterogeneity between identical twins showed that this variability is not genetic but seems to be due to environmental agents (Cheung et al 2018).

So in this new hypothesis for aging, there appears to be random epigenetic drift that is not determined by the type of allele or any specific environmental factor. Random epigenetic drift may be the cause of the various phenotypes associated with aging, as different genes are randomly repressed or ectopically activated. Mistakes in the DNA methylation process accumulate with age and may be responsible for the deterioration of our physiology and anatomy. If this is so, some genes may be more important targets than others. (The above-mentioned estrogen receptors, for instance, are critical not only in the vascular system but also for skeletal and muscular health.)

This has important corollaries. For instance, age is the most significant risk factor for most cancers and heart attacks. Recent studies (Lind et al 2018; Kresovich et al 2019) have found that biological age, as measured by DNA methylation, was significantly associated with increased risk of developing cardiovascular disease and breast cancer. It is not known what mechanisms set the rate of random DNA methylation, but these may be critically important for regulating aging both within and between species.2

Stem Cells and Aging

One of the hallmarks of aging is the declining ability of stem cells and progenitor cells to restore damaged or nonfunctioning tissues. A decline in muscle progenitor (satellite) cell activity is seen when Notch signaling is lost, resulting in a significant decrease in the ability to maintain muscle function. Similarly, an age-dependent decline in liver progenitor cell division impairs liver regeneration due to a decline in transcription factor cEBP. And the age-associated graying of mammalian hair appears to be due to the apoptosis of melanocyte stem cells in the hair bulge niche (Nishimura et al. 2005; Robinson and Fisher 2009). One of the questions, then, becomes: Is this part of the aging syndrome caused by the declining function of stem cells or by a declining ability of the stem cell niche to support them?

One way to test this is by “fusing” an old mouse to a young mouse. This can be done by a technique called parabiosis, wherein the animals’ circulatory systems are surgically joined so that the two mice share one blood supply. If an aged and a young mouse are parabiosed—a technique called heterochronic parabiosis—the stem cells of the old mouse are exposed to factors in young blood serum (and vice versa). Heterochronic parabiosis has been seen to restore the activity of old stem cells. Notch signaling of the muscle stem cells regained its youthful levels, and muscle cell regeneration was restored. Similarly, liver progenitor cells regained “young” levels of cEBP—and with it their ability to regenerate (Conboy et al. 2005; Conboy and Rando 2012). Young blood promoted the repair of aged spinal cords, reversed the thickening (hypertrophy) of the heart walls, and stimulated the formation of new neurons in aged mice (Figure 7; Villeda et al. 2011, 2014; Ruckh et al. 2012).

After S. A. Villeda et al. 2011. Nature 477: 90–94.

Figure 7 Factors in plasma (the liquid portion of blood) of old mice alter the development of new neurons and behaviors in young mice. (A) Protocol whereby plasma from young mice is injected into other young mice (left), or plasma from old mice is injected into young mice (right). (B) Young mice receiving young plasma continue to manufacture new neurons (dark stain), whereas the number of new neurons decreases in young mice injected with old plasma. (C) In training to do a particular task, mice receiving young or old plasma initially had the same number of errors. One day later, mice that received young plasma remembered their former mistakes and made fewer errors than mice that received old plasma.

Loffredo and colleagues (2013) identified the “rejuvenating” blood-borne agent as paracrine factor GDF11, an extracellular signaling protein. GDF11 circulates through the blood of young mice, and its levels decline with age. When GDF11 was transfused into older mice, the youthful levels reversed age-related hypertrophy. In the brain, GDF11 appeared to counteract some of the deterioration of aging; injecting GDF11 into older mice increased brain capillary production, neuron formation, and olfactory discrimination (Figure 8; Katsimpardi et al. 2014; Poggioli et al. 2015).

From Katsimpardi et al. 2014. Science 344: 630–634, courtesy of L. Katsimpardi and L. Rubin

Figure 8 A possible “rejuvenating” agent. The blood-borne paracrine factor GDF11 promotes vascular remodeling (A) and neurogenesis (B) in the mouse brain. Micrographs show a region of the dentate gyrus of the brain stained for new capillaries or neural stem cells. The GDF11-treated brains were from 22-month-old (elderly) mice injected with GDF11 for 4 weeks.

Since the stem cells are not transfused from one animal to the other, it appears that GDF11 helps the function of the stem cell niche. It is not yet known whether GDF11 (or young blood plasma in general) extends the lifespan or improves the health of mice or humans (see Scudellari 2015). There is also the danger that, when working with stem cells, there is a fine balance between underproliferation (leading to aging) and over-proliferation (leading to cancer). While folklore is full of old vampires retaining their youth through young blood, there is no scientific evidence for this technique working in humans (or for that matter, long-term in mice) (Robbins 2018) .

Exceptions to the Aging Rule

There are a few species in which aging seems to be optional, and these may hold some important clues to how animals can live longer and retain their health. Turtles, for instance, are a symbol of longevity in many cultures. Many turtle species not only live a long time, they don’t seem to undergo a typical aging syndrome. Turtles seem to have “negligible senescence,” in that their mortality rate does not increase with age, nor does their reproductive rate decrease with age. In these species, older females lay at least as many eggs as their younger counterparts. Miller (2001) showed that a 60-year-old female three-toed box turtle (Terrapene carolina triunguis) lays as many eggs annually as she ever did. If turtle telomeres shorten with age, it happens (like so many turtle things) extremely slowly (Girondot and Garcia 1998; Hatase et al. 2008). Interestingly, turtles have special adaptations against oxygen deprivation, and these enzymes also protect against ROS (Congdon et al. 2003; Lutz et al. 2003; Krivoruchko and Storey 2010). When the genome of a giant tortoise became available, Quesdad and colleagues (2019) found that many of its immune system genes had been duplicated, and several tumor suppressor genes and genes encoding DNA repair enzymes had been expanded, as well. Rather than have one system enhanced, it appears that turtles may be using several means to extend their longevity. It took decades of research to demonstrate that turtles age, but Warner and colleagues (2016) found that although the number of eggs the turtle lays does not decrease, their probability of hatching diminishes as the mother turtle gets older.

In monarch butterflies (Danaus plexippus), adults that migrate to wintering grounds in the mountains of central Mexico live several months (August–March), whereas their summer counterparts live only about 2 months (May–July). The regulation of this difference appears to be juvenile hormone (JH; Herman and Tatar 2001). The migrating butterflies are sterile because of suppressed synthesis of JH. If migrants are given JH in the laboratory, they regain fertility but lose their longevity. Conversely, when summer monarchs have their corpora allata removed so they can no longer make JH (see Chapter 21), their longevity increases 100%. Mutations in the insulin signaling pathway of Drosophila likewise decrease JH synthesis (Tu et al. 2005). This decrease in JH makes the flies small, sterile, and long-lived, adding to whatever longevity-producing effect protection against ROS might have.

Finally, there may be organisms, especially among the cnidarians, that can actually cheat death. Certain hydra appear to be immortal, retaining their stem cell populations (Li et al 2018). The hydrozoans Turritopsis dohrnii and Hydractinia carnea are two cnidarian species known to have evolved a remarkable variation on this theme. These organisms have both a polyp stage (similar to the hydra) and a medusa (“jellyfish”) stage. In most hydrozoan species, the polyp stage gives rise the sexual medusa stage. The medusae then produce gametes that spawn the next generation and, like most adults, they senesce and die. However, the medusae of T. dohrnii and H. carnea can revert to the polyp stage after becoming sexually mature (Bavestrello et al. 1992; Piraino et al. 1996), a feat called reverse development (Schmich et al. 2007). The multilayered medusa essentially dedifferentiates to become a two-layered ball-like stage similar to that of a larva before becoming a polyp and then develops into a polyp itself (Figure 9).

After Schmich et al. 2007

Figure 9 Life cycle of Turritopsis dohrnii and Hydractinia carnea. In the normal life cycle of cnidarians, the colonies of polyps bud off medusa (jellyfish) into the sea water. After a period of planktonic life, the mature medusa release their gametes. Fertilization occurs and the mature medusa dies. The embryo forms a larva (planula), which then transforms itself into a ball-like stage from which a new polyp emerges. In T. dohrnii and H. carnea, the medusa can dedifferentiate into a ball-like stage, which can generate a polyp and start the life cycle again (“reverse development”; red arrows).

Next Step Investigation

Several interacting agents may promote longevity. These include calorie restriction, protection against oxidative stress, factors activated by a suppressed insulin pathway, and factors affected by decreased mTORC1 signaling (e.g., decreased protein translation and augmented autophagy). Stem cells and their niches may play critical roles, as well. The next step is to integrate these into pathways that might predict the lifespan of organisms and to aid individuals to live a healthy life to the very end (Gage et al 2016; Shetty 2018). Unless attention is paid to this general aging syndrome, we risk ending up like Tithonos, the miserable wretch of Greek mythology to whom the gods awarded eternal life but not eternal youth.

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1. When Social Security benefits were established in the United States in 1935, the average working citizen died before age 65. Thus, he (and it usually was a he) was not expected to get back as much as he had paid into the system. Similarly, marriage “until death do us part” was easier to achieve when death occurred in the third or fourth decade of life. Before antibiotics, the death rate of young women due to infections associated with childbirth was high throughout the world.

2. This video discusses epigenetic regulation of aging https://www.youtube.com/watch?time_continue=17&v=a20ljuYpcj8

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