The Science of Aging
To be alive is to age. It’s one trait we share with every living thing on Earth, and have since the dawn of time. And yet, the process of aging remains one of the great mysteries of biology.
In people as well as animals, researchers are still struggling to understand why organisms age and what happens inside of their bodies as they grow older. The questions are legion: Why do some people remain active and alert at 100, while others decline and pass away decades earlier? Why do some animals, such as giant tortoises and bowhead whales, count their lives in centuries while so many other species survive only a handful of years? And, ultimately, what can we do about it? Can the effects of aging be reversed or be made less debilitating?
Already, horses today have longer lives than they did just a few decades ago—and they tend to be healthier late in life. But there is more work to be done. Researchers continue to investigate how the passage of time affects the function of cells, immunity and metabolic processes.
Ultimately, this work may yield information that helps us care for horses in ways that maximize their longevity, but much remains to be learned. “It would be nice to have some biomarkers of aging that would be helpful to the owner—to know how well or not well their horse is aging,” says Amanda Adams, PhD, of the Gluck Equine Research Center at the University of Kentucky. “This is an interesting but challenging area of research.”
Still, studies conducted at Gluck as well as Rutgers University in New Jersey and other research centers around the world are yielding insights into aging that are already beginning to offer new possibilities for keeping our horses sounder and more comfortable into their later years. And opportunities for better care will likely only improve in the years to come. “Our mission is to improve the health and well-being of the horse,” says Adams.
1. Chronic InflammationOne of the more significant changes in an aging body is the occurrence of chronic, low-grade inflammation, a phenomenon called inflamm-aging. “Unlike acute inflammation, chronic inflammation is not resolved within minutes or hours but involves immune responses and cytokine production contributing to this mild, persistent inflammatory process that leads to tissue degeneration,” explains Adams. In people, this chronic inflammation is believed to be related to a host of ailments that become more common with advancing age, such as osteoarthritis, heart disease, diabetes, changes in body composition, energy production and utilization, metabolic homeostasis, immunosenescence, neuronal health and certain cancers. In horses, inflamm-aging may play a role in the development of many conditions, including arthritis, inflammatory airway diseases, Cushing’s and insulin resistance.Then again, inflamm-aging may simply be a side effect of these conditions—its causes and effects are still not understood. “This low-grade, chronic inflammatory process occurs with increasing age, and we don’t know why,” says Adams. “There are several theories, and one is that chronic antigenic stimulation over the years has basically worn out the immune system. There is breakdown in the signaling pathways that may contribute to the inflamm-aging that occurs with age, and we are trying to understand what may or may not contribute to this, and what it means for the horse.” Researchers are investigating how diet, hormones and other factors may influence this phenomenon. “Maybe there’s a nutritional component, or some kind of lack in nutrients as we age that contributes to the inflamm-aging response,” Adams says. “Is there a connection between pituitary pars intermedia dysfunction [PPID, also called Cushing’s disease] and inflamm-aging? Is there an association between loss of muscle mass and inflamm-aging? It’s been shown in human studies that with increasing age there is loss of muscle mass, and we’ve also seen this in horses: Older horses with higher levels of inflamm-aging have more muscle loss. We are also looking at whether inflamm-aging contributes to any of the arthritis problems that older horses are faced with.” A seasonal effect? One study from Gluck produced some surprising results, suggesting that inflamm-aging may be influenced by changes in season. “We are looking at the impact of the seasons on immune response, such as T-cell proliferation responses and inflamm-aging responses, because we found significant impacts of season in both young and old horses on these immune responses,” says Adams. “The seasonal research components came out of an unrelated eight-month study in which we were sampling the horses monthly and found some changes we weren’t expecting. We found much different levels of inflammation than we did the month before. We examined everything closely and nothing had changed—except the season.” That finding led to further investigation. “We designed a study with the primary focus to examine the effect of season on immune responses in horses,” Adams says. “We just finished this year-long research and were able to measure differences in immune responses with season in both young and older horses. The inflammation levels peak in spring and drop during late summer months through winter and then come back up in the spring.” With this said, she adds that there was still an age-associated increase of inflammation or inflamm-aging.It is not yet known what, if any, effects these findings might have on a horse’s health. “We are trying to understand if there is any crosstalk with the hormone responses because we know that season also affects hormone production,” Adams says. “We are looking at whether we can modulate the rise and fall in inflammation.”
Not surprisingly, research suggests that excessive weight may play a role in the development of chronic inflammation. In fact, obese older horses have been found to have higher frequencies of lymphocytes and monocytes that produce inflammatory cytokines than do thinner older horses, suggesting that increased fat levels contribute to inflamm-aging. Reducing the body weight and fat tissue in these older horses significantly reduced the levels of inflammatory agents.
Practical implicationsIt might seem obvious that you’d reduce inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs), but scientists are not yet ready to make that recommendation. “We have conducted in vitro [laboratory] studies and, yes, have found that polyphenols and NSAIDs can modify or have a significant effect on inflamm-aging, but we have yet to conduct in vivo, or in-the-horse, studies, so at this time we cannot make any recommendations on which of the natural anti-inflammatory products may be helpful to the old horse,” says Adams. “We hope to know more of these answers soon.”Long-term, low doses of NSAIDs are sometimes prescribed to control arthritis pain in older horses, but in part due to the risk of side effects, for now at least they are not recommended for horses without specific medical needs. Many equine supplements, especially those formulated to support healthy joints, contain ingredients with anti-inflammatory properties. These include glucosamine, avocado soybean unsaponifiables (ASU), hyaluronan (HA), MSM (methylsulfonylmethane) and omega-3 fatty acids as well as herbals such as yucca, devil’s claw and grape seed extract. The effects, if any, of supplements like these on chronic, low-level inflammation are not yet known, but generally, these products fall into the category of “can’t hurt; might help.” More research is needed to answer the unknowns.It does seem clear, however, that if a horse is overweight, reducing his excess body fat will help limit his pro-inflammatory factors and keep him healthier overall. If your aging horse is overweight, talk to your veterinarian about an appropriate diet and exercise plan to help him lose extra pounds.
2. REDUCED IMMUNITYAn inevitable effect of aging is immunosenescence, the technical term for a decline in immune function, which leads to greater vulnerability to illness and infection. “There is breakdown in the actual function of immune cells,” says Adams. “One of the things research has shown is that there is reduced T-cell function—there are fewer T-cells to undergo proliferation.” T-cells, or T-lymphocytes, are a type of white blood cell integral to immune function. When T-cells encounter a foreign pathogen for the first time, they multiply rapidly and release large numbers of proteins called cytokines that attract other immune cells to help neutralize the threat. After the infection subsides, a certain number of T-cells “remember” how to quickly create new antibodies to respond to that antigen. “We have a small pool of those ‘memory cells’ that remain in our lymph nodes and lymphatic system in other areas of the body. These cells are very important because whenever the body is faced with an invasion by viruses or bacteria, this small pool of cells has to undergo proliferation to divide and form more cells—to make that pool larger so they can take care of the infection,” Adams explains. “If this can’t happen at an optimal rate or level, the animal might succumb to the infection, or it might take the body longer to recover from infections,” she adds. “There is more chance for secondary infections to occur, especially if the primary infection is viral, like influenza. The horse may develop secondary bacterial infections.”
One consequence of this reduced immune activity is that older horses may not get the full protective effect of vaccinations. “If we have a breakdown in immune responses to vaccination, the horse is at risk—especially if he is still being shown and exposed to other horses,” Adams says. “More specifically, duration of immunity post-vaccination may be different for an older horse compared to younger horses. A hallmark characteristic of immunosenescence is reduced responsiveness to vaccination as well as to infectious agents, and this is one of the things our research has been and is currently looking at,” she adds. “A lot of work has been done showing how horses respond to equine influenza vaccination. It’s been shown that older horses have reduced responses, but not much work has been done to show how they respond to other vaccines such as West Nile virus. So we are looking at this, and also—based on human medicine—at how horses respond to different formulations of vaccine.” That is, aging horses may have different responses to various types of vaccines—modified-live virus versus killed vaccines, for example. “In addition we are looking at how endocrinopathies such as PPID affect immune responses to vaccination,” Adams says. “About 30 percent of aged horses are affected by equine Cushing’s, and we know that this plays a role in suppressing or changing immune function. There has not been much work done yet in comparing PPID horses with non-PPID age-matched control horses and how their immune systems may or may not be different, and how they respond to vaccinations, but we are currently working on this.” These studies have so far yielded some intriguing and unexpected results. “We do see some changes in how some PPID horses respond to vaccinations, but not as much as we thought we would. We performed a study looking at how PPID horses respond immunologically to a multivalent vaccine so we could look at different immune responses to different antigens. The PPID horses did not respond any differently to the influenza component of the vaccine, but there were some differences in how they responded to the herpesvirus and the West Nile components,” Adams says.“The PPID horses’ antibody titers dropped. So we measured their immune responses post-vaccination and based on preliminary analysis we found that the PPID horses didn’t hold their antibody titers as long as the non-PPID horses. This is something we are investigating further.”
Parasite control challengeAnother significant aspect of a horse’s immune function involves internal parasites. Young horses develop immunity to ascarids and other internal parasites as they mature, but does a weakening immune system mean older horses might again become more vulnerable? “We recently conducted an experiment to evaluate whether old horses demonstrate statistically higher fecal egg counts, compared to middle-aged adult horses, and to investigate systemic expression of pro-inflammatory cytokines in old and middle-aged horses treated with different dewormers,” says Adams. The researchers found that the older horses did have significantly higher fecal egg counts than the middle-aged adults, and egg counts declined in both groups following deworming. “We wanted to measure immune responses post-deworming, but we didn’t see anything as dramatic as we thought we would, although we didn’t measure some of the immune responses important for parasite resistance,” Adams says. “We were mainly wanting to see if there were differences in fecal egg counts, and how older horses respond to dewormers.”
Practical implications Ask your veterinarian to review your aged horse’s vaccination schedule. “If you own an older, at-risk horse this might mean potentially vaccinating more often, but you’d want to work with your veterinarian regarding how often,” says Adams. For example, she adds, “A person might think about boosting that horse with West Nile vaccine at six months rather than just annually, especially in a region with a long mosquito season.” Likewise, take extra care with your parasite control program. Perform fecal egg counts to determine when to deworm and which type of anthel-mintic to use. Finally, consider implementing some additional measures to protect old horses from illnesses and infections. Simple biosecurity and hygiene measures are a good start. You may want to keep the older “homebodies” separate from horses who travel to shows and other public venues, and it’s always a good idea to keep a separate set of buckets, tack and grooming tools for each horse in your care.If your older horse still competes, consider spraying down his showgrounds stall with a disinfectant before placing him in it. Also, avoid sharing buckets, tack or tools with others, and don’t let anyone borrow yours. Discourage visitors from petting your horse, and don’t let him have nose-to-nose contact with other horses. 3. EXERCISE INTOLERANCEYou probably don’t need researchers to tell you that the body’s athletic capabilities diminish with age. But striving to understand exactly how and why that happens may help improve a horse’s quality of life. “We have shown that aerobic capacity does decline with age,” says Karyn Malinowski, PhD, director of the Rutgers Equine Science Center at Rutgers University. “[We’ve] done many studies on the use of exercise and exercise training/conditioning, trying to ameliorate some of the negative effects of aging.”One of the more significant aging-related changes is hormonal in origin. “We have shown changes in the hypothalamic-pituitary-adrenal axis [HPAA] in that cortisol0 response post-exercise is lower in the old horse compared to the younger horse,” says Malinowski. The HPAA is a network of feedback interactions among three glands: the hypothalamus, the pituitary and the adrenals. Hormones secreted from each gland stimulate the secretion of additional hormones from the others, and together these hormonal fluctuations help to regulate processes including digestion, immunity and physiological responses to stress. “Nettie Liburt, a graduate student in our lab, identified the place where the system was broken, and it was at the level of the adrenal gland,” says Malinowski. “Corticotropin-releasing factor is still released from the hypothalamus, and ACTH [adrenocorticotropic hormone] is still released from the pituitary in normal amounts, but the adrenal gland cannot respond. This has a huge implication for metabolic response to exercise because glycogen0 stores are mobilized from the liver in response to cortisol. So the older horse can’t refuel his skeletal muscles as quickly as a younger horse can. And since cortisol has a very strong anti-inflammatory effect in pain management, the older horse is at a disadvantage. Since the anti-inflammatory properties of cortisol are missing, as well as the fuel mobilization properties from cortisol stimulation, the older horse cannot recover from exercise as quickly as the younger horse.” As a result, the older horse will be stiffer and more sore than a younger horse who does a comparable amount of exercise.Chronic inflammation also appears to have an effect on an aging horse’s response to exercise. “Interleukin-1 beta is a general inflammatory cytokine that you want to see rise after exercise,” says Malinowski. “What we saw in the older horse is that this response is reduced or blunted. This has implications for recovery from acute exercise. An older horse can’t recover as quickly as a younger one.”
Practical implications Although regular exercise is not a magic elixir, it actually can slow or even reverse nearly all age-related changes. “You can actually start to restore insulin sensitivity, and restore a bit more health to the immune system, and can certainly change the HPAA axis and have a bit more response to exercise in cortisol concentration post-exercise. The only thing that we didn’t see a positive response from exercise was in immune response,” says Malinowski. “The group of horses we were studying here had an average age of 27, so they truly were older horses. You can still increase aerobic capacity and reduce body fat in an older horse with exercise conditioning and training. Exercise is a great thing for a senior horse’s health.”If your aging horse has always been fit and seems to be doing well, there’s no need to change his exercise regimen, though you’ll want to keep his advancing years in mind. That may mean easing back on the amount of intense work in favor of longer, slower rides, as well as giving him more time to recover and rest after exertion. Icing or cold hosing your horse’s legs after rides can ease inflammation and reduce his stiffness in the long run. Also, be particularly careful to avoid allowing him to overheat. Another effect of aging is a decline in the body’s capacity for thermoregulation, which is the process of heating and cooling to maintain its core temperature. Older horses will overheat more readily when they exercise, and they may take longer to cool off after working in hotter weather. Avoiding riding during the hottest parts of the day, and even on moderately warm days be prepared to hose and scrape down your horse to help him cool and recover more quickly.Above all, keep your old horse as active as possible for as long as possible. Ask your veterinarian for guidance on the best program for an older horse who is overweight, unfit, arthritic or has other lameness issues. But keep in mind that exercise tends to be beneficial in most cases. “People who keep their older horses in stalls and do nothing with them are not doing them a favor. These older horses need to be outside and moving,” says Malinowski. “We can help reduce percent body fat, body weight and decrease the discomfort from arthritis. We haven’t done joint taps to look at arthritis, but from just watching old horses work on the treadmill and then turning them out, you know they feel better. They are running around and bucking and having a great time. The next day, they are waiting by the gate wanting to come in for their next session!” 4. NUTRITIONAL FACTORSOne of the newer fields of study in aging is nutritional immunology—which examines how foods might influence immune function and inflamm-aging. We tend to focus on the role the gut plays in digestion, but the entire lining of the gastrointestinal tract, as well as the liver, is populated with specialized immune cells, collectively called gut-associated lymphoid tissue (GALT). In fact, by some estimates in other species, upwards of 60 to 70 percent of the immune system is located in the gut. So it would make sense that the nutrients a horse eats, or lacks, might influence the functions of those immune cells. Further, the interaction between the gut microbiota and the immune system is important to consider. Healthy gut microbes may mean a healthy immune system. Researchers are only just beginning to investigate these links, and some results have been promising.“We are looking at whether we can improve immune responses to vaccination and modulate the inflamm-aging responses with nutrition,” says Adams. “We have shown some positive changes—such as our work with pro-biotics and prebiotics.” In a couple of studies done in collaboration with Purina Animal Health, administering prebiotics—nutrients that not only have immunomodulatory activities but also encourage the growth or activity of beneficial microorganisms in the gut—improved the responses of older horses to vaccines. “We did measure some improved immune responses to vaccination and some reduced inflammation,” says Adams. “Nutritional changes helped a little, and we were excited.”Adams and other researchers are continuing to explore how various nutrients and dietary supplements influence a horse’s inflammation and immune status. “We are looking at the impact of plant-based immunomodulators like the polyphenol compounds [curcumin , quercetin, etc.] that are being used in human medicine,” she says. “We’ve done an in vitro study where we compared incubating immune cells [from old horses] with these different compounds. We stimulate these cells and look at how much inflammation they can produce in the presence of each compound. We also had some samples set up with bute and Banamine in vitro and found that several of these compounds were able to reduce inflammation very similarly to bute or Banamine. In fact, some of them were better at it than these drugs.”Eventually, studies like these may lead to alternative methods of treating inflammation that would not run the risk of the side effects drugs like bute and Banamine can cause. “Most owners would love to be able to put their older horses on something that is safe and works in terms of reducing inflammation and perhaps improving any lameness or soreness due to age-associated arthritis,” says Adams. “We were excited to show that some of these compounds are very good at reducing inflammation in vitro, and we’re hoping now to do more in vivo work looking at some of these compounds in aged horses. We want to see if any have the potential to modulate inflammation.”
Practical implications Specific dietary recommendations based on nutritional immunology are still on the horizon. But we do know that horses benefit from some added nutrients. “For older horses it’s a good idea to supplement with certain vitamins,” says equine nutritionist Shannon Pratt-Phillips, PhD, of North Carolina State University. “Many people supplement their senior horses with vitamin E and/or fish oil [for the DHA and other omega-3 fatty acids].” Another common supplement, which is also included in many senior feeds, is vitamin C. Normally, horses manufacture all the vitamin C they need in their livers. However, says Pratt-Phillips, “A study found that older horses had lower vitamin C status. It is unknown whether the older horses are deficient because they can’t make their own vitamin C as well anymore, or whether they have a higher turnover because they are older and have more inflammatory processes going on in the body. Perhaps the older horse simply needs more vitamin C and this is why the status is low.”
Horses who remain healthy and active well into their 30s are common these days—many can continue to perform well in a number of disciplines. As we learn more about how their bodies age, perhaps we’ll find more and better ways to keep them going strong for years to come.
This article first appeared in EQUUS issue #461, February 2016.