Wither youth

Why does skin grow old?

Beauty is only skin deep, right? So no wonder people care so much about how their skin looks. Over $140 billion a year is spent globally on cosmetics. In 2011 there were 4.1 million Botox procedures in the United States, 718,000 chemical peels, more than a half-million laser skin procedures, 672,000 microdermabrasions (a kind of ultra-gentle sandblasting of the skin), 153,000 eyelid surgeries and a bunch of face-lifts. You get the idea.

Whatever skin may lack in depth, it makes up for it by covering a lot of territory. A typical person’s skin is stretched over 20 or 22 square feet of surface area, about the size of a standard doorway. Your skin is the largest organ in your body, weighing about 8 pounds. It buffers you against the elements and insults of the outside world, locks out toxins and pathogens, locks in body fluids, senses the tactile environment, regulates body temperature via sweating, makes vitamin D — and just plain keeps you structurally intact by enveloping your fat, organs and bones.

Dermatologist Anne Chang, MD, is working hard to break down the wall between aesthetic dermatology (the dermatology of appearance) and geriatric dermatology (the dermatology of aging). Her research into the underlying causes of skin aging holds implications not just for slowing or reversing the superficial effects of that aging process but also, quite possibly, for staving off a host of age-related skin diseases including skin cancer.

Our skin reveals a lot about us to ourselves and to others. It reflects our mood — it flushes when we’re embarrassed; it turns livid with rage. It also provides a clue about our age.

As we get older our skin does, too. It gets thinner, less elastic, subject to discoloration. Cells that produce collagen, a key structural element in skin, make less of it and replicate less often.

The terrain of aging skin grows all too familiar with the passing years: bags under the eyes, crow’s feet, jowls, tiny tangles of blood vessels, ever more pronounced pores and pits and pigmentation irregularities. Then there are wrinkles — long, deep “frown lines” radiating upward from the inside edges of the eyebrows and “laugh lines” that trace a furrow from our nostrils to the edges of our lips in our 40s, and finer lines that start crisscrossing our faces in our 50s. Sagging skin gets more prominent in our later years as we lose bone and fat.

And it’s all right there on the very outside of us, where everyone else can see it.

That’s just fine with Anne Chang. “One of the nice things about skin is that it’s amenable to direct inspection,” she says. “You can look at it. That makes it a great proving ground for evidence-based medicine.” It’s also a plus when it comes to following doctor’s orders. “Patients care about skin because they can see it. So they’re motivated to try to improve their condition. When they see things working, that’s positive feedback for them to continue doing what they’re supposed to be doing.”

Anne Chang, MD

Skin can tell you about what’s going on inside of you, too. “Lots of diseases have cutaneous manifestations,” Chang says. Sometimes itchy skin means liver or kidney trouble. Dry skin can signify thyroid trouble. Scaling of the hands and feet, blistering, or rashes around the mouth can be signs of cancer in an internal organ.

Aging puts skin at an ever higher risk of problems in its own right. In particular, the incidence of three different types of skin cancer — basal cell carcinoma, squamous cell carcinoma and melanoma — increases with age. Rates of melanoma, by far the most deadly of the trio, rise dramatically after age 50. So slowing the aging process in skin is not merely a cosmetic concern. It’s a health issue.

Chang says, “We’ve been asking, can you turn back time? Can aging effects be reversed? Can you rejuvenate skin, make it young again?” Some 40 million American baby boomers age 65 and older, and probably a fair number of people younger than that, would like to know, too.

Same ol’, same ol’

The standard bromides for keeping your skin young are about the same as the ones for staying healthy in general: Eat a good diet. Quit smoking. Avoid pollution. Manage stress. Get some sleep.

There is one special arrow of advice aimed directly at your skin: Stay out of the sun. If you’re going to get exposed, wear sunblock or sun-protective clothing.

Unquestionably, different histories of exposure to sunlight, pollution, smoking and nutrients lead to different outcomes. Then again, says Chang, stick a fair-skinned, redheaded person in strong sunlight for 20 minutes and they’ll burn. Put a dark-skinned person in the sun for the same amount of time, and the consequences will be less severe.

Although that’s a no-brainer, Chang says our responses to all kinds of exposures are in no small part conditioned by underlying genetic predispositions. “We’re bombarded with marketing that says you can improve your skin if you buy this or that. But there’s more to the story than just external treatments or therapies,” she says. Genes are a big part of it. “But nobody’s ever found what those genes are that keep our skin healthy.”

Well, that’s no longer quite true, thanks to Chang herself.

Our birthday suit

What is this thing called skin, which we wear day and night from the time we come out of the womb until the day we die?

Skin is a highly organized organ consisting of two layers: an outer one called the epidermis and an underlying one called the dermis.

The epidermis is itself a multilayered tissue, and an active one. At its base are stem cells that can generate daughter cells that gradually get pushed upward through several epidermal layers, during which migration they lose moisture content. By the time they reach the surface, they’ve flattened and coalesced into a tough, waterproof coat of dead cells called the stratum corneum. A person sheds 40,000 of these dead skin cells (called squamous cells) each minute of the day. Successive layers below the stratum corneum host various cell types including squamous cells and melanocytes, which make a dark pigment that protects against ultraviolet light. In the deepest layer of the epidermis, the stratum basale, new squamous cells are formed.

Below the epidermis lies the dermis, which contains collagen-producing fibroblasts, lymph and blood vessels, touch receptors, immune cells, sweat glands and sebaceous glands, which produce an oily substance called sebum that keeps skin moist.

What all cell types have in common is that their molecular contents are prone to damage by a ubiquitous chemical reaction called oxidation that can produce electron-rich chunks of broken molecules that, Chang says, rattle around like little firecrackers and cause damage, breaking some molecules apart and smooshing others together. Either way, it can be bad for a cell. Among the agents triggering oxidation are not only oxygen, as one might surmise, but sunlight, air pollution, cigarette smoke and the plain old everyday process of converting the food we eat into the energy and chemicals that all the cells in our body use. Get used to it. There’s no way around it.

A major internal source of oxidant chemicals as well as other cell-irritating substances is inflammation, a crucial part of the immune response that tends to slip into overdrive as we grow older. A few years ago, Chang spearheaded a study that measured 46 middle-aged Japanese women’s blood levels of metabolites called isoprostanes, produced from the breakdown of inflammatory substances called prostaglandins. Because they circulate in the blood, isoprostane levels are an accessible proxy for systemic inflammation. And sure enough, the women with the “oldest” skin for their age had the highest isoprostane levels in their blood, which strongly suggests an inflammatory component to skin aging. Prostaglandins are manufactured by an enzyme that is blocked by aspirin, ibuprofen and other so-called NSAIDs (for “nonsteroidal anti-inflammatory drugs”). Chang hopes to test such a drug for its anti-aging effects on skin.

To find out what the underlying genetic drivers of the aging process in skin might be, Chang launched a study in collaboration with Nir Barzilai, MD, professor of medicine and director of the Institute for Aging Research at Albert Einstein College of Medicine in the Bronx, who has assembled a cohort of some 600 centenarian Ashkenazi Jews (technically, they’re between ages 95 and 112) along with their children and children’s spouses, in order to explore the molecular wellsprings of longevity.

A requirement for participation in Barzilai’s ongoing project is that all four of a potential subject’s grandparents have to have been Ashkenazis: descended from a “founder group” of some 30,000 northern and eastern Europe-dwelling Jews in the 17th century who had survived plagues and pogroms over several centuries. Having until recently married almost strictly among themselves for the entirety of their long European residency, Ashkenazi Jews have remarkably homogeneous genetic backgrounds. This makes them ideal for studying whatever genetic differences do crop up among them, including differences in genes associated with aging, according to Barzilai. “We want to know why some people age quickly and others age slowly,” he says.

A key first step toward figuring that out is finding genes that, when they don’t work right, leave the skin more vulnerable to the ravages of the environment. This, in turn, could lead to better understanding of the aging process in skin and — via hard work, luck, or both — drugs and procedures that stave off superficial effects of aging as well as life-threatening age-related skin diseases.

The fact that so many of Barzilai’s subjects are very old was hugely beneficial for Chang’s purposes. The older you get and the longer your skin is exposed to internal and external factors influencing its aging, the easier it gets to spot the signs of aging written on the skin and to differentiate those whose skin is aging slowly from those whose skin is not.

“One of our centenarians was 48 years older than you would expect her skin to look based strictly on chronological age,” Barzilai says.

His New York-based team shipped photographs of a number of Ashkenazi subjects of various ages to Chang’s lab at Stanford, where her team classified individuals according to standard dermatological measures of skin aging such as relative abundance of wrinkles and sagging.

Then they separated the subjects into two groups: 218 whose skin was aging the most slowly relative to their actual age, and the 210 other participants with more rapidly aging skin. Chang and her associates obtained blood cells from the subjects, analyzed the DNA, and compared the largely similar genomes of the two groups, keeping their eye out for tiny gene variants that were over- or under-represented in one group or the other.

They found three genes in which the presence of particular variants was associated with a differential likelihood of people’s skin being old or young for their age. None of these genes had previously been implicated as aging-related. In fact, not all that much is known about any of them. One seems to be involved in immune function. A second gene has been tied to a condition called premature ovarian insufficiency, an arguably aging-related condition in which women run out of ova before reaching the typical age of menopause onset. And the third gene appears to be associated with the ability of fibroblasts — collagen-producing cells — to dodge their suicidal response to certain stresses. “These genes are not associated with longevity per se,” says Barzilai. “They don’t come up when we look at very long-lived people versus those who die young.”

“It turns out centenarians don’t necessarily have better skin-aging genes than younger groups,” says Chang. “There’s a different set of genes for skin aging. Skin youthfulness, cardiac health, glucose metabolism — these don’t necessarily all go together.”

Chang wants to do further experiments along these lines using skin samples from individuals with and without these gene variants. “Looking at blood is like looking at a fossil,” she says. “You’re guessing about what’s going on in skin based on indirect evidence.” Using skin rather than blood will allow Chang to directly explore what these genes’ protein products are doing inside skin cells.


In March 2009, Chang attended a gala event celebrating the Department of Dermatology’s 50th anniversary. So did a large number of physicians who had completed their residencies in the department before moving on to institutions far and wide. Among them was Patrick Bitter, MD, an alumnus of Stanford’s medical school who completed his dermatological residency here in 1986. Now in private practice, Bitter is the co-inventor of a commercially available procedure called broadband light therapy, or BBL. (About $215 million was spent on BBL treatments in the United States in 2009.) Approved by the Food and Drug Administration for ridding skin of redness, discoloration and unwanted hair, BBL employs a hand-held device that directs high-intensity light in the visible and infrared frequencies at the area of skin needing treatment.

Bitter was well aware that BBL works — it’s used millions of times a year in the United States with reliable cosmetic success — but was wondering if anybody there might be able to help him figure out exactly how. Above all, he wished to know whether the treatment was purely superficial and short term, or whether the visible results reflected an underlying rejuvenation process.

All experts acknowledge that ultraviolet light is rough on skin. But what about the rest of the rainbow? Might visible and infrared light’s effects be not only benign but beneficial?

In 2007, Stanford dermatology professor Howard Chang, MD, PhD, and some colleagues blocked the action of a protein complex called NF-kappa-B in the epidermis of mice. NF-kappa-B is a molecular “master switch” that, when activated, causes wholesale shifts in which genes in a cell are turned on and which are dormant. Chang and his associates found that blocking it rendered old mice’s skin more youthful looking.

Bitter had heard a talk Howard Chang had given about his experiments with mice and was curious about whether BBL might be exerting an anti-aging effect on human skin by, for example, blocking NF-kappa-B there. But how to bridge this gap between clinical practice and basic science? Anne Chang had already proposed to explore the phenomenon in humans, and was looking for ways to study that question.

Another collaboration was born. In 2013 Anne Chang was the lead author of a paper on which Bitter was the second author and Howard Chang was the senior author. In that study, the researchers got skin biopsies from the forearms of five older women with moderate to severe photoaging damage and five younger women with no signs of photoaging on their arms, then used a laboratory technique to estimate the activity levels of each of the 22,000 or so genes in the cells making up every woman’s biopsy sample. After the older women had undergone a course of BBL treatment, the investigators again took biopsy samples from them.

They found almost 2,300 genes whose output differed significantly in old versus young women. More striking, BBL improved not only the visible appearance of the older women’s skin — less fine wrinkling and discoloration, and an overall healthier look to the professional eye — but also restored the activity levels of about 1,300 of the 2,300 age- and damage-altered genes of the older women’s skin to a semblance of their “youthful” counterparts’ profile.

“We could detect those changes a full six weeks later,” Anne Chang says. “These treatments, rather than just making the surface of the skin look better, may actually have anti-aging effects.” She says she’d like to study these patients at six months or one year after treatment to find out how long the effect lasts.

One could speculate that it might not be such a bad idea to slather on a ton of sunblock and then soak up lots of sun every day. Although that could well turn out to be correct, Chang isn’t suggesting it. Just which wavelengths of light are exerting exactly which effect on which biochemical pathways remains to be nailed down. For her part, Chang is digging deeper into the question of precisely what molecular mechanisms are driving the seemingly inexorable aging of skin and how it might be prevented, slowed, stopped or turned around.

Interestingly, a healthy number of genes whose activity levels are altered by aging and, in reverse, by BBL are known to be under the influence of NF-kappa-B, suggesting that BBL might indeed be having at least some of its restorative effect by messing with that key pro-inflammatory transcription factor.

Howard Chang is well-known in scientific circles for pioneering the exploration of so-called long noncoding RNAs, or lncRNAs (pronounced “link” RNAs), which instead of coding for proteins, as do most other lengthy RNA molecules, act directly on the genome. He’s shown that lncRNAs play a key role in determining which genes in a cell will be active or remain dormant. A recent study led by Anne Chang analyzed skin samples from 120 women of northern European descent who live in the San Francisco Bay Area and range in age from 18 to 93. In this study Chang and her colleagues (including Howard Chang) isolated a new variety of lncRNA that is most scarce in individuals with younger appearing skin. The discovery potentially unlocks the door to a totally new way of controlling skin aging: manipulating levels of this lncRNA molecule in skin through drugs or other approaches.

Looking ahead, Chang hopes to explore the degree to which the genes she has associated with aging skin may also be associated with aging in any of the body’s internal organs. She’s also started compiling her own registry of Ashkenazi Jews located in the San Francisco Bay Area.

This skin-aging business is a lot more than skin deep to Chang. “Nearly 74,000 new melanoma cases are expected this year,” she says. “The rate of melanoma among American men in their 80s is double that of men in their 60s. Melanoma is a disease of aging and, more than that, a disease of aging skin. There may be ways to prevent or reverse that process. Youthful skin is more than a cosmetic convenience.” Millions of aging baby boomers, gazing into the bathroom mirror, nod their heads in wistful agreement.

Bruce Goldman is a science writer for the medical school’s Office of Communication & Public Affairs. Email him at goldmanb@stanford.edu.

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